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

摘要：射血分数保留性心力衰竭（HFpEF）正在成为主要形式 然而，我们没有为患者提供治疗方法，使他们的运动耐量有限， 和生活质量。虽然对心肌给予了很多关注，但数据表明， 骨骼肌（SkM）氧利用率也有助于这种情况下的劳力不耐受。此外，委员会认为， 在HFpEF患者中已经证实了降低的一氧化氮（NO）生物利用度。无垫块SkM 氧气输送，并在增强脂肪酸氧化（FAO）中发挥关键作用，这两者对于 次极量运动耐力最近，钠-葡萄糖协同转运蛋白-2抑制剂如恩格列净 （EMPA）在其他心血管疾病患者中表现出显着的益处，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中特异性鉴定的靶向异常，包括：（a）线粒体生物合成增加，（B） 增加FAO，（c）增加血浆酮体，提供额外的乙酰辅酶A能量来源 生产，和（d）增加血液血红蛋白，增加任何给定血流的氧气输送。 此外，由于NO对FAO是必不可少的，并且是运动SkM血流量的关键介导者，我们建议， 将EMPA与硝酸钾（KNO 3）等NO供体结合使用将改善运动效果 与单独EMPA或活性对照相比，HFpEF患者的容量。 我们的总体假设是受损的SkM氧化磷酸化能力（OxPhos）限制了 HFpEF的运动耐量。在本建议中，我们将重点放在次极量运动耐力上， 运动更好地反映了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，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53名HFpEF参与者中进行随机双盲交叉试验， 试验：（1）EMPA;（2）EMPA + KNO 3;和（3）氯化钾（活性对照）。目标1：参与者将 进行自行车测力运动测试。主要终点将是次极量运动的变化 耐力在目标2中：我们将使用MRI测试我们的3种干预措施对SkM OxPhos的影响， 跖屈运动还将采用新的MRI序列来量化肌内灌注。在 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， 量化SkM蛋白质组，提供体外评估，以支持我们的运动测量。 我们的建议将靶向HFpEF中的SkM代谢，并全面评估与HFpEF的关系。 SkM OxPhos和次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治疗。

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.