Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction
29 Pages Posted: 23 Mar 2022 Publication Status: Preprint
Abstract
Objectives: Determine the safety and tolerability of the nicotinamide-adenine dinucleotide (NAD+) precursor, nicotinamide riboside (NR), and whether NR increases NR and NAD+ blood levels in participants with ACC/AHA Stage C heart failure with reduced ejection fraction (HFrEF).
Background: Mitochondrial dysfunction in heart failure is associated with alterations in intracellular levels of NAD+ and NADH. In mouse HFrEF models, NAD+ precursor supplementation blunts decline in cardiac function. No studies have examined the long-term safety and tolerability of NAD+ precursors in humans with Stage C HFrEF.
Methods: In a 12-week, randomized, placebo-controlled trial, 30 participants with Stage C HFrEF were randomized to either NR or matching placebo (2:1 allocation ratio). Participants were monitored for symptoms, laboratory values, blood NR/NAD+ levels, and exploratory endpoints. Mitochondrial respiratory function and inflammatory marker expression were assessed in participant peripheral blood mononuclear cells (PBMCs).
Results: There were no between-group differences in on-trial rates of adverse events or laboratory values. On-trial compliance was high, and the NR group had significantly higher blood NAD+ levels (NR: 30±20 vs. Placebo: -0.3±2 µmol, P<0.00001). There were no between-group differences in six-minute walk distance, LV function or quality of life score. In the NR group, relative NAD+ level increases correlated with increases in PBMC basal (R2=0.41, P=0.003) and maximal (R2=0.43, P=0.0022) respiration, and with decreased PBMC expression of the pro-inflammatory protein, NLRP3 (R2=0.33, P=0.02).
Conclusions: NR was safe, well-tolerated, and increased whole blood NAD+ levels. Relative blood NAD+ level increases correlated with improved mitochondrial function and decreased inflammatory marker expression in PBMCs.
Keywords: Nicotinamide Riboside, NAD, Heart Failure with Reduced Ejection Fraction, Sterile Inflammation, Mitochondrial Function
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