Multidrug Metabolic Approach to Improve Exercise and Skeletal Muscle 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，使他们在运动耐力方面受到限制 和生活质量。虽然心肌已经受到了很大的关注，但数据表明， 在这种情况下，骨骼肌(SKM)的氧气利用也会导致运动不耐受。此外， HFpEF患者的一氧化氮(NO)生物利用度降低。不增加SKM 氧传递和在促进脂肪酸氧化(FAO)方面发挥关键作用，这两项都对 亚极量运动耐力。最近，钠-葡萄糖共转运体-2抑制剂，如依帕格列平 (Empa)在其他心血管疾病患者中显示出显著的好处，尽管它们在 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 在HFpEF中明确的靶异常，包括：(A)增加线粒体的生物发生，(B) 增加粮农组织，(C)增加血浆酮小体，提供额外的乙酰辅酶A能源 (D)增加血液中的血红蛋白，增加任何特定血流的氧气输送。 此外，由于NO对粮农组织是必不可少的，也是运动SKM血液流动的关键调节因子，我们建议 将EMPA与硝酸钾(KNO3)等非供体物质相结合，将会改善运动 HFpEF患者的容量，与EMPA单独使用或主动对照相比。 我们的主要假设是SKM氧化磷酸化能力受损(OxPhos)限制了 高周负压运动耐量试验。在这个建议中，我们将重点放在次最大运动耐力上 运动更能反映HFpEF患者在日常活动中达到的消耗水平，是更多的 依赖粮农组织比最大努力锻炼，更不可能受到心输出量限制的限制。 我们将在53名HFpEF参与者中随机双盲交叉测试三种干预措施的影响 试验：(1)EMPA；(2)EMPA+KNO3；(3)氯化钾(主动对照)。目标1：参与者将 进行自行车测功性运动测试。主要终点将是次极量运动的变化 忍耐力。在目标2中，我们将使用以下MRI测试我们的三种干预措施对SKM OxPhos的影响 足底屈曲练习。还将采用新的MRI序列来量化肌肉内的灌注。在……里面 目的3：我们将进行SKM组织活检，以评估线粒体呼吸，SKM代谢组，以及 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SKM的代谢，并全面评估两者之间的关系 SKM OxPhos和使用互补技术的亚极量运动耐力之间的关系。这项建议 有可能将SKM代谢确定为这种疾病的重要治疗靶点 目前还没有批准的药物疗法。

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.