Targeting Skeletal Muscle Perfusion and Oxidative Capacity in HFpEF

HFpEF 中的靶向骨骼肌灌注和氧化能力

基本信息

批准号：
10625968
负责人：
Payman Zamani
金额：
$ 78.75万
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：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625968
关键词：
Acceleration 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 Goals Heart failure Heterogeneity Impairment Individual Intervention Intramuscular Kinetics Left Levocarnitine Life Magnetic Resonance Imaging Measurement Measures Metabolic Mitochondria Movement Muscle Nitrates Oxidative Phosphorylation Oxygen Patients Perfusion Persons Pharmacotherapy Phenotype Potassium Chloride Process Production Quality of life Randomized Skeletal Muscle Syndrome Techniques Testing Therapeutic Therapeutic Intervention Time Translating Work active control diagnostic strategy disability endurance exercise exercise capacity impaired capacity improved individual response insight nicotinamide-beta-riboside novel novel diagnostics novel therapeutics pharmacologic potassium nitrate preservation prevent primary endpoint propionyl-coenzyme A response secondary endpoint success supplemental oxygen treatment response 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. 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：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，我们的初步数据表明，心力衰竭存在异常。骨骼肌氧化磷酸化能力（SM OxPhos）可能导致 SM 运动不耐受。 OxPhos 是一个复杂的指标，结合了 (a) 肌内灌注和 (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，我们在 HFpEF 的骨骼肌活检样本中发现了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精力充沛缺陷并损害线粒体储备。该提案的目标是研究 SM OxPhos 与次极量运动之间的关系在 HFpEF 中，科学前提是 SM OxPhos 的改进将转化为我们专注于次最大耐力运动，因为这更好地反映了耐力运动的改善。 HFpEF 患者在日常活动中达到的运动水平目标 1：我们将测试三种干预措施。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与烟酰胺核苷（NR）和丙酰-L-肉碱的组合（PLC），通过补充肌肉内灌注和线粒体氧化储备能力来靶向已确定的代谢物缺陷；以及（3）氯化钾（活性对照）。 KNO3 和联合治疗将改善次最大耐力运动，联合治疗将导致我们还将评估我们的干预措施对 SM OxPhos 的影响以及两者之间的关系。 SM OxPhos 和次最大耐力运动之间的关系在目标 2 中：我们将测试一种新的诊断策略来确定特定 HFpEF 患者 SM OxPhos 受损的潜在机制：对补充氧气（100% O2） SM OxPhos 缺乏对氧气的反应表明我们发现，这些患者会因线粒体储备而阻碍额外氧气的利用。通过解决线粒体储备问题，从联合疗法（KNO3+NR+PLC）中获得更大的益处除了增加肌内灌注。我们的提案将全面评估 SM OxPhos 和次极大值之间的关系它将使用补充技术来测试治疗性小说，其主要目标是改善次最大运动量，并确定哪些耐力患者应该接受哪种治疗。该提案有可能改变 HFpEF 治疗的前景，为我们提供了一个机制为这些原本有限的患者提供缓解的合理策略。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Predictive Ability of Pressure-Corrected Arterial Stiffness Indices: Comparison of Pulse Wave Velocity, Cardio-Ankle Vascular Index (CAVI), and CAVI0.

压力校正动脉僵硬度指数的预测能力：脉搏波速度、心踝血管指数 (CAVI) 和 CAVI0 的比较。

DOI：
发表时间：
2022-03-08
期刊：
影响因子：
3.2
作者：
Spronck, Bart;Obeid, Mary Jo;Paravathaneni, Mahati;Gadela, Naga Vaishnavi;Singh, Gurpreet;Magro, Caroline A;Kulkarni, Varsha;Kondaveety, Soumya;Gade, Keerthi Chandrika;Bhuva, Rushik;Kulick;Sanchez, Nicolas;Akers, Scott;Chirinos
通讯作者：
Chirinos

Prospective Evaluation of Cardiovascular Risk 10 Years After a Hypertensive Disorder of Pregnancy.

妊娠期高血压疾病 10 年后心血管风险的前瞻性评估。

DOI：
发表时间：
2022-06-21
期刊：
影响因子：
24
作者：
Levine, Lisa D;Ky, Bonnie;Chirinos, Julio A;Koshinksi, Jessica;Arany, Zoltan;Riis, Valerie;Elovitz, Michal A;Koelper, Nathanael;Lewey, Jennifer
通讯作者：
Lewey, Jennifer

Matrix GIa Protein, Large Artery Stiffness, and the Risk of Heart Failure With Preserved Ejection Fraction.

基质 Gla 蛋白、大动脉僵硬度以及保留射血分数的心力衰竭风险。