The Effect of Nicotinamide Riboside on Skeletal Muscle Function in Heart Failure Subjects
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|ClinicalTrials.gov Identifier: NCT03565328|
Recruitment Status : Terminated (Slow/insufficient accrual and investigators have left the study.)
First Posted : June 21, 2018
Results First Posted : October 28, 2020
Last Update Posted : October 28, 2020
People are living longer and are more likely to survive a heart attack if they have one. Longer life expectancy is good but it also means more people get chronic heart failure over time. This is a condition in which the heart doesn't pump blood as well as it should. Treatment of chronic heart failure has not improved much in a few decades. Researchers want to see if giving a dietary supplement to people with heart failure can help their heart function. The supplement is nicotinamide riboside (NR).
To study how NR affects skeletal muscle function in people with heart failure.
Adults ages 18-70 with clinically stable systolic heart failure
Participants will be screened with a medical history and physical exam. They will answer demographic questions and review their current medical treatments. They will have blood and urine tests. They will have an echocardiogram. This uses sound waves to test heart function.
Participants will have 8 study visits over 16 weeks. At these visits, they will have some of the following:
Repeat of screening tests
Skin sample taken
Skeletal muscle exercise Nuclear magnetic resonance (NMR) spectroscopy. Muscles will be measured while participants do foot exercises.
Cardiopulmonary exercise testing. Participants may ride a stationary bike or walk on a treadmill. A facemask will analyze their breath. Heart and blood pressure measurements will be taken.
Participants will take the supplement in pill form each day for 12 weeks. Pill bottles will be checked at study visits.
Participants should not significantly change their activity levels during the study.
|Condition or disease||Intervention/treatment||Phase|
|Heart Failure||Dietary Supplement: Nicotinamide Riboside||Phase 2|
As life expectancy increases and acute cardiac mortality decreases, the incidence of chronic heart failure (HF) continues to rise, and despite this, conceptual advances in the treatment of chronic heart failure have not increased substantially over last few decades. One intracellular component of heart failure progression is mitochondrial bioenergetic dysfunction. Although the mechanism underpinning this is not completely understood, recent metabolomics data demonstrated an incomplete flux of metabolites through oxidative phosphorylation (OX PHOS) in HF. In parallel, data has shown that hyperacetylation of mitochondrial bioenergetic enzymes, with the concomitant blunting of enzymatic activity is evident in HF. Putting these together, an emerging hypothesis implicates excessive acetylation of mitochondrial proteins with the subsequent blunting of bioenergetic enzyme function, as a mechanism underpinning incomplete flux through OX PHOS resulting in HF progression.
In parallel with cardiac bioenergetic deficiency chronic HF subjects display disrupted skeletal muscle OX PHOS, which is thought to contribute towards overall fatigue and reduced exercise tolerance. Interestingly exercise training in HF subjects improves skeletal muscle mitochondrial OX PHOS capacity and subject activity levels. Exercise training additionally increases activity of the mitochondrial regulatory deacetylase sirtuin enzymes SIRT1 and SIRT3, in parallel with improved skeletal muscle OX PHOS capacity. At the same time HF-associated disruption in skeletal muscle metabolic function activates skeletal muscle cytokine production. These inflammatory programs, in turn, are proposed to contribute towards impaired functional capacity in HF. Interestingly, and mirroring improved OX PHOS following exercise programs in HF studies, exercise training similarly reduces skeletal muscle inflammatory effects.
Biochemical and bioenergetic consequences of impaired mitochondrial OX PHOS leads to decreased NAD+ levels, which exacerbate mitochondrial dysfunction by inactivating the NAD+ dependent sirtuin enzymes. Experimental studies using NAD+ precursors to increase NAD+ production have been shown to normalize NADH/NAD+ ratios and activate Sirtuin enzymes, resulting in enhanced OX PHOS with beneficial effects in numerous systems including skeletal muscle and in the blunting of inflammation.
In this pilot study we will directly assess the effect of the NAD+ precursor, nicotinamide riboside (NR) on skeletal muscle mitochondrial OX PHOS in HF subjects using: skeletal muscle Nuclear magnetic resonance (NMR) spectroscopy assessment of the rate of high energy phosphate recovery in response to submaximal exercise; assessment of the effect of NR on functional capacity using cardiopulmonary exercise testing (CPET) to determine VO(2max) and anaerobic threshold; evaluation of the NR effect on serum metabolomics at rest and in response to CPET; and by measuring circulating cytokine levels pre- and post- NR administration. These studies would enable a more comprehensive assessment of the role for NR supplementation on skeletal muscle mitochondrial function in subjects with systolic HF
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||2 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Pilot Study to Evaluate the Effect of Nicotinamide Riboside on Skeletal Muscle Function in Heart Failure Subjects|
|Actual Study Start Date :||September 27, 2018|
|Actual Primary Completion Date :||November 18, 2019|
|Actual Study Completion Date :||November 18, 2019|
Experimental: Nicotinamide Riboside in patients with stable heart failure
Nicotinamide Riboside (NR) will be started at 500 mg daily (250 mg BID) then increased at two weekly intervals by 250 mg/dose (BID) (500 mg/day) to a final dose of 1000 mg PO BID (2000 mg/day) in patients with stable, systolic heart failure.
Dietary Supplement: Nicotinamide Riboside
Nicotinamide Riboside (NR) will be started at 500 mg daily (250 mg BID) be increased at two weekly intervals by 250 mg/dose (BID) (500 mg/day) to a final dose of 1000mg PO BID (2000 mg/day).
Other Name: Niagen; Nicotinamide Riboside (NR)
- Number of Participants Who Had Enhancement of Mitochondrial Function in Skeletal Muscle [ Time Frame: baseline-12 week-16 week ]Number of participants who had enhancement mitochondrial function in skeletal muscle Nuclear magnetic resonance (NMR) spectroscopy will be performed at baseline, at the end of the 12-week Nicotinamide Riboside (NR) supplementation period and repeated 4 weeks post-NR washout.
- Measure the Effects of Nicotinamide Riboside (NR) on Oxidative Phosphorylation and Inflammation in Respective Subject Primary Skin Fibroblasts [ Time Frame: Baseline, 12 week ]Measure the effects in participants of Nicotinamide Riboside (NR) on oxidative phosphorylation and inflammation in respective subject primary skin fibroblasts
- Number of Participants Without Heart Failure Linked Inflammation [ Time Frame: Baseline, 12 week ]To quantitative serum cytokine immunoassay profiling to assess whether Nicotinamide Riboside (NR) blunts heart failure (HF) linked inflammation
- Number of Participants Who Experienced an Increased Rate of Oxidative Phosphorylation [ Time Frame: Baseline, 12 week ]Serum quantitative metabolomic profiling, pre and post-cardiopulmonary exercise testing (CPET) to evaluate whether Nicotinamide Riboside (NR) increases the rate of oxidative phosphorylation
- VO2 Max and Anaerobic Thresholds [ Time Frame: Baseline, 12 week ]Analysis of VO2max and the anaerobic threshold will be measured.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03565328
|United States, Maryland|
|Walter Reed National Military Medical Center|
|Bethesda, Maryland, United States, 20889|
|National Institutes of Health Clinical Center|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Michael N Sack, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|