Targeting Skeletal Muscle Perfusion and Oxidative Capacity in HFpEF

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，但我们没有治疗方法为患者提供。我们的初步数据显示， 骨骼肌氧化磷酸化能力(SM OxPhos)可能与运动耐量有关。SM OXPHOS是一个复杂的指标，包括(A)肌肉内灌注和(B)线粒体氧化 储备能力，这表明需要对两者进行衡量，以了解SM背后的机制 OXPHOS损伤。我们小组开发了新的MRI序列，可以评估这两种测量。 此外，我们在HFpEF的骨骼肌活检样本中发现了一种独特的代谢物特征。 患者：NAD+和丙酰辅酶A减少，表明代谢紊乱可能导致能量 缺乏线粒体储备，损害线粒体储备。 这项建议的目的是调查SM OxPhos和次极量运动之间的关系 HFpEF的耐力，科学前提是SM OxPhos的改进将转化为 提高运动耐力。我们把重点放在次极限运动耐力上，因为这更好地反映了 HFpEF患者在日常活动中达到的用力水平。在目标1中：我们将测试三种干预措施 53名HFpEF受试者进行交叉试验：(1)主要针对运动的硝酸钾(KNO3) (2)硝酸钾与烟酰胺核苷(NR)和丙酰-L-肉碱的联合应用 (PLC)，通过补充以肌肉内灌注和线粒体氧化储备能力为靶点 已确定的代谢物缺陷；以及(3)氯化钾(主动对照)。我们假设，虽然两者 硝酸钾和联合疗法将提高亚极量运动耐力，联合疗法将导致 整体涨幅更大。我们还将评估我们的干预措施对SM OxPhos的影响，以及与 SM OxPhos和亚极量运动耐力之间的关系。在目标2中：我们将测试一种新的诊断策略 确定特定HFpEF患者SM OxPhos受损的机制：对 补充氧气(100%O2)。SM OxPhos对氧气缺乏反应表明 线粒体储备阻止了额外氧气的利用。我们假设这些病人会 通过解决线粒体储备问题，从联合治疗(KNO3+NR+PLC)中获得更大好处 除了增加肌肉内的灌流。 我们的建议将全面评估SM OxPhos和次极大之间的关系 使用免费的技巧锻炼耐力。它将测试新的疗法，主要目标是 改善次极量运动耐力，并确定哪些患者应该接受哪种治疗。 这项提议有可能改变HFpEF疗法的面貌，给我们一个机械的 合理的策略，为这些原本有限的患者提供缓解。

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.