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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：
10096631
负责人：
Payman Zamani
金额：
$ 78.61万
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/10096631
关键词：
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 Failure Goals Heart failure Heterogeneity Impairment Individual Intervention Intramuscular Kinetics Lead Left Levocarnitine Life Magnetic Resonance Imaging Measurement Measures Metabolic Mitochondria Movement Muscle Nitrates Oxidative Phosphorylation Oxygen Patients Perfusion Pharmacology Pharmacotherapy Phenotype Potassium Chloride Process Production Quality of life Randomized Skeletal Muscle Syndrome Techniques Testing Therapeutic Therapeutic Intervention Time Translating Work active control base disability endurance exercise exercise capacity impaired capacity improved individual response insight nicotinamide-beta-riboside novel novel diagnostics novel drug combination novel therapeutics 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：保留射血分数的心力衰竭（HFpEF）正在成为主要形式