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Principal Investigator: Payman Zamani
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $770,206
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Acceleration><Acetyl Carnitine><Acetylcarnitine><Address><Aerobic><Biochemical><Biopsy Sample><Biopsy Specimen><Blood><Blood Reticuloendothelial System><Clinical Trials><Combined Modality Therapy><Complex><Cross-Over Trials><Crossover Trials><Data><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Drug Combinations><Drug Therapy><EFRAC><Ejection Fraction><Exercise><Exercise Tolerance><Exertion><Goals><Heart failure><Heterogeneity><Impairment><Individual><Intervention><Intervention Strategies><Intramuscular><Kinetics><L Carnitine><Left><Levocarnitine><Life><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metabolic><Mitochondria><Movement><Multimodal Therapy><Multimodal Treatment><Muscle><Muscle Tissue><NMR Imaging><NMR Tomography><NO3-><Nitrates><Nuclear Magnetic Resonance Imaging><O element><O2 element><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen><Patients><Perfusion><Persons><Pharmacotherapy><Phenotype><Potassium Chloride><Process><Production><QOL><Quality of life><Randomized><Skeletal Muscle><Syndrome><Techniques><Testing><Therapeutic><Therapeutic Intervention><Time><Translating><Vitamin B T><Voluntary Muscle><Work><Zeugmatography><active control><body movement><cardiac failure><combination therapy><combined modality treatment><combined treatment><diagnostic approach><diagnostic strategy><disability><drug treatment><endurance exercise><exercise capacity><impaired capacity><improved><individual response><individualized response><insight><intervention therapy><interventional strategy><mitochondrial><multi-modal therapy><multi-modal treatment><muscular><new diagnostics><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation diagnostics><next generation therapeutics><nicotinamide ribonucleoside><nicotinamide ribose><nicotinamide riboside><nicotinamide-beta-riboside><nitrate><novel><novel diagnostics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pharmacologic><potassium nitrate><preservation><prevent><preventing><primary end point><primary endpoint><propionyl-CoA><propionyl-coenzyme A><randomisation><randomization><randomly assigned><response><response to therapy><response to treatment><saltpetre><secondary end point><secondary endpoint><success><supplemental oxygen><therapeutic response><therapy response><treatment response><treatment responsiveness><uptake>