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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

基本信息

批准号：
10642954
负责人：
Payman Zamani
金额：
$ 69.39万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10642954
关键词：
Acetyl Coenzyme A Activities of Daily Living Adipose tissue Animal Model Aorta 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 Fatty Acids Glucose Goals Heart failure Hemoglobin Imaging Techniques Impairment In Vitro Individual Intervention Intramuscular Ketone Bodies Ketones Kinetics Life Link Magnetic Resonance Imaging Measurement Measures Mediating Mediator Metabolic Metabolism Mitochondria Muscle Muscle Fibers Muscle Mitochondria Myocardium Nitric Oxide Nitric Oxide Donors Nonesterified Fatty Acids Oxidative Phosphorylation Oxygen Oxygen Consumption Palmitates Participant Pathway interactions Patients Perfusion Permeability Persons Pharmaceutical Preparations 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 electric impedance endurance exercise exercise capacity exhaustion fatty acid oxidation functional disability improved in vivo in vivo imaging inhibitor insight metabolome novel oxidation pharmacologic potassium nitrate preservation prevent primary endpoint protein expression respiratory restoration skeletal muscle metabolism symporter targeted treatment therapeutic target uptake

项目摘要

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：射血分数保留的心力衰竭 (HFpEF) 有望成为主要形式心力衰竭，但我们无法为患者提供治疗方法，使他们的运动耐量受到限制和生活质量。虽然心肌受到了很多关注，但数据表明，心肌的异常骨骼肌 (SkM) 的氧利用也会导致这种情况下的运动不耐受。而且， HFpEF 患者的一氧化氮 (NO) 生物利用度降低已得到证实。 NO 增强 SkM 氧输送并在增强脂肪酸氧化 (FAO) 方面发挥关键作用，这两者对于次最大运动耐力。最近，钠-葡萄糖协同转运蛋白 2 抑制剂如恩格列净（EMPA）已在其他心血管疾病患者中表现出显着的益处，尽管它们的使用 HFpEF 仍不清楚。 EMPA 可能通过多种机制对 HFpEF 患者有益，其中许多机制 HFpEF 中特别发现的目标异常，包括：(a) 增加线粒体生物发生，(b) 增加FAO，(c) 增加血浆酮体，提供乙酰辅酶A的额外能量来源 (d) 增加血液中的血红蛋白，增强任何给定血流的氧气输送。此外，由于NO对于FAO至关重要，并且是运动SkM血流的关键调节因子，因此我们建议将 EMPA 与硝酸钾 (KNO3) 等一氧化氮供体结合将改善运动与单独使用 EMPA 或主动对照相比，HFpEF 患者的能力。我们的首要假设是 SkM 氧化磷酸化能力 (OxPhos) 受损会限制 HFpEF 的运动耐量。我们在本提案中重点关注次最大运动耐力作为次最大运动耐力运动量更能反映 HFpEF 患者在日常活动中达到的运动水平，更能反映 HFpEF 患者在日常活动中达到的运动水平。与最大努力运动相比，它更依赖于FAO，并且不太可能受到心输出量限制的限制。我们将在随机双盲交叉试验中测试三种干预措施对 53 名 HFpEF 参与者的影响试验：（1）EMPA； (2)EMPA+KNO3； (3)氯化钾（活性对照）。目标 1：参与者将接受自行车测功运动测试。主要终点是次最大运动量的变化耐力。目标 2：我们将使用 MRI 测试 3 种干预措施对 SkM OxPhos 的影响，如下所示跖屈练习。新型 MRI 序列也将用于量化肌内灌注。在目标 3：我们将进行 SkM 组织活检来评估线粒体呼吸、SkM 代谢组和量化 SkM 蛋白质组，提供体外评估来支持我们的运动测量。我们的提案将针对 HFpEF 中的 SkM 代谢并全面评估其关系使用互补技术在 SkM OxPhos 和次最大运动耐力之间进行比较。这个提议有潜力将 SkM 代谢确定为我们针对的这种疾病的重要治疗靶点目前尚无批准的药物疗法。