Targeting Skeletal Muscle Perfusion and Oxidative Capacity in HFpEF

HFpEF 中的靶向骨骼肌灌注和氧化能力

• 批准号: 10096631
• 负责人: Payman Zamani
• 金额: $ 78.61万
• 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: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10096631
• 关键词: Acetylcarnitine; Address; Aerobic; Biochemical; Biopsy Specimen; Blood; Clinical Trials; Combined Modality Therapy; Complex; Cross-Over Trials; Data; Double-Blind Method; Drug Combinations; EFRAC; Exercise; Exercise Tolerance; Exertion; Failure; Goals; Heart failure; Heterogeneity; Impairment; Individual; Intervention; Intramuscular; Kinetics; Lead; Left; Levocarnitine; Life; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Mitochondria; Movement; Muscle; Nitrates; Oxidative Phosphorylation; Oxygen; Patients; Perfusion; Pharmacology; Pharmacotherapy; Phenotype; Potassium Chloride; Process; Production; Quality of life; Randomized; Skeletal Muscle; Syndrome; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Work; active control; base; disability; endurance exercise; exercise capacity; impaired capacity; improved; individual response; insight; nicotinamide-beta-riboside; novel; novel diagnostics; novel drug combination; novel therapeutics; potassium nitrate; preservation; prevent; primary endpoint; propionyl-coenzyme A; response; secondary endpoint; success; supplemental oxygen; treatment response; 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. Our preliminary data suggest that abnormalities in skeletal muscle oxidative phosphorylation capacity (SM OxPhos) may contribute to exertional intolerance. SM OxPhos is a complex metric, incorporating both (a) intramuscular perfusion and (b) mitochondrial oxidative reserve capacity, suggesting that both need to be measured to understand the mechanism underlying SM OxPhos impairment. Our group has developed novel MRI sequences which can evaluate both measures. Moreover, we have identified a unique metabolite signature in skeletal muscle biopsy samples from HFpEF patients: a reduction in NAD+ and Propionyl-CoA, indicating metabolic perturbations that may lead to energetic deficits and impair mitochondrial reserve. The goal of this proposal is to investigate the relationship between SM OxPhos and submaximal exercise endurance in HFpEF, with the scientific premise that improvements in SM OxPhos will translate into improvements in exercise endurance. We focus on submaximal exercise endurance as this better reflects the level of exertion reached by HFpEF patients during daily activities. In Aim 1: We will test three interventions in 53 subjects with HFpEF in a cross-over trial: (1) Potassium nitrate (KNO3), which predominantly targets exercise intramuscular perfusion; (2) The combination of KNO3 with nicotinamide riboside (NR) and Propionyl-L-Carnitine (PLC), which targets both intramuscular perfusion and mitochondrial oxidative reserve capacity by replenishing the identified metabolite deficiencies; and (3) Potassium chloride (active control). We hypothesize that while both KNO3 and combination therapy will improve submaximal exercise endurance, combination therapy will lead to greater overall increases. We will also assess the impact of our interventions on SM OxPhos, and the relationship between SM OxPhos and submaximal exercise endurance. In Aim 2: we will test a new diagnostic strategy to identify the mechanism underlying a specific HFpEF patient’s impaired SM OxPhos: the response to supplemental oxygen (100% O2). The lack of SM OxPhos response to oxygen suggests that an impairment in mitochondrial reserve is preventing the utilization of additional oxygen. We hypothesize that these patients will derive greater benefit from combination therapy (KNO3+NR+PLC) by addressing mitochondrial reserve in addition to increasing intramuscular perfusion. Our proposal will comprehensively assess the relationship between SM OxPhos and submaximal exercise endurance using complimentary techniques. It will test novel therapeutics, with the primary goal of improving submaximal exercise endurance and also identify which patients should be treated with which therapy. This proposal has the potential to change the landscape of HFpEF therapeutics, giving us a mechanistically rational strategy to offer relief to these otherwise limited patients.

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，但我们没有提供患者的治疗方法。我们的初步数据表明异常 骨骼肌氧化磷酸化能力（SM OXPHOS）可能有助于静动性。 SM Oxphos是一种复杂的度量，既包含（a）肌肉内灌注和（b）线粒体氧化 储备能力，表明两者都需要测量以了解SM的机制 Oxphos损害。我们的小组开发了新的MRI序列，可以评估这两种措施。 此外，我们已经确定了来自HFPEF的骨骼肌肉活检样品中独特的代谢物签名 患者：NAD+和丙酰辅酶A的减少，表明代谢扰动可能导致能量 缺陷和损害线粒体储备。 该提议的目的是研究SM Oxphos与次最大运动之间的关系 HFPEF的耐力，科学前提是，SM Oxphos的改进将转化为 运动耐力的改善。我们专注于次最大运动耐力，因为这更好地反映了 HFPEF患者在日常活动中达到的劳累水平。在AIM 1中：我们将测试三个干预措施 在交叉试验中有53名HFPEF受试者：（1）硝酸钾（KNO3），主要针对运动 肌内灌注； （2）KNO3与烟酰胺核糖苷（NR）和丙酰L-Carnitine的组合 （PLC），靶向肌内灌注和线粒体氧化储备的能力 确定的代谢产物缺陷； （3）氯化钾（主动对照）。我们假设这两个 KNO3和联合疗法将改善次最大运动耐力，联合疗法将导致 总体增长更大。我们还将评估干预措施对SM oxphos的影响，以及关系 在Sm oxphos和次最大运动耐力之间。在AIM 2中：我们将测试一种新的诊断策略 确定特定HFPEF患者的Sm sm axphos的机制：对 补充氧（100％O2）。缺乏对氧气反应的SM氧气反应表明 线粒体储备可防止使用额外的氧气。我们假设这些患者将 通过解决线粒体储备在联合疗法（KNO3+NR+PLC）中获得更大的好处 增加肌肉内灌注。 我们的建议将全面评估SM Oxphos与次最大的关系 使用免费技术运动耐力。它将测试新疗法，其主要目标是 改善次最大运动耐力，并确定应通过哪种治疗治疗哪些患者。 该建议有可能改变HFPEF治疗的景观，从而使我们有机械的 为这些原本有限的患者提供缓解的合理策略。