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: 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
• 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

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，异常 骨骼肌氧化磷酸化能力（SM OxPhos）可能导致运动不耐受。 SM 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 氧化磷酸损伤。我们的小组开发了新的 MRI 序列，可以评估这两种测量值。 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 HFpEF 的耐力，其科学前提是 SM OxPhos 的改进将转化为 运动耐力的改善。我们关注次最大运动耐力，因为这更好地反映了 HFpEF 患者在日常活动中达到的运动水平。目标 1：我们将测试三种干预措施 一项交叉试验中有 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），其目标是通过补充肌内灌注和线粒体氧化储备能力 已确定的代谢缺陷； (3)氯化钾（活性对照）。我们假设虽然两者 KNO3 和联合治疗将提高次最大运动耐力，联合治疗将导致 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，以及两者之间的关系 SM OxPhos 和次最大运动耐力之间的关系。目标 2：我们将测试一种新的诊断策略 确定特定 HFpEF 患者 SM OxPhos 受损的潜在机制：对 补充氧气（100% O2）。 SM OxPhos 对氧气反应的缺乏表明 线粒体储备阻碍了额外氧气的利用。我们假设这些患者将 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 使用补充技术锻炼耐力。它将测试新的疗法，主要目标是 提高次最大运动耐力，并确定哪些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

Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction.

• DOI: 10.3389/fcvm.2022.1016452
• 发表时间: 2022
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6

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

• DOI: 10.1016/j.jacc.2022.03.383
• 发表时间: 2022-06-21
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 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

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

• DOI: 10.1093/ajh/hpab168
• 发表时间: 2022-03-08
• 期刊: American journal of hypertension
• 影响因子: 3.2
• 作者: Spronck B;Obeid MJ;Paravathaneni M;Gadela NV;Singh G;Magro CA;Kulkarni V;Kondaveety S;Gade KC;Bhuva R;Kulick-Soper CM;Sanchez N;Akers S;Chirinos JA
• 通讯作者: Chirinos JA

Arterial Stiffness and Diabetes Risk in Framingham Heart Study and UK Biobank.

• DOI: 10.1161/circresaha.122.320796
• 发表时间: 2022-09-02
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Cohen JB;Mitchell GF;Gill D;Burgess S;Rahman M;Hanff TC;Ramachandran VS;Mutalik KM;Townsend RR;Chirinos JA
• 通讯作者: Chirinos JA

Association of blood pressure variability with Endothelin-1 by menopause status among Black women: findings from the Jackson Heart Study.

黑人女性绝经状态下血压变异性与内皮素 1 的关联：杰克逊心脏研究的结果。

• DOI: 10.1038/s41371-023-00824-y
• 发表时间: 2023
• 期刊: Journal of human hypertension
• 影响因子: 2.7
• 作者: Rethy,Leah;Polsinelli,VincenzoB;Muntner,Paul;Bello,NatalieA;Cohen,JordanaB
• 通讯作者: Cohen,JordanaB