Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

To definitively demonstrate the effects of increasing NAD+ levels in HF patients, this randomized, placebo-controlled trial of NR in 40 participants scheduled for elective LVAD surgery with the underlying hypotheses that those randomized to NR will have higher myocardial NAD+ levels, improved mitochondrial function, restored gene expression and reduced inflammatory response as compared to participants randomized to placebo. To this end, the study has the following specific aims: Aim 1: Randomize 40 participants undergoing elective LVAD placement into a double-blind, placebo-controlled study of NR vs. placebo at an NR:placebo ratio of 2:1. 1. Participants will have labs (including safety panels) drawn at baseline (Day 1), with NR or placebo dose escalation to 1000mg twice daily by Day 3, and the last dose administered the evening prior to surgery. 2. Final labs will be drawn on the day of surgery, and samples of fresh cardiac tissue removed from the left ventricular apex during LVAD implantation surgery will be collected in the operating room. Aim 2: Determine the effect of NR vs. placebo on NAD(H) levels, mitochondrial function and its regulation through epigenetic modifications in the failing myocardium. 1. Measure NAD+ and NADH levels in the blood and myocardium of the participants. 2. Assess mitochondrial morphology and function in cardiac tissue using electron microscopy (EM) and isolated mitochondria. 3. Determine changes in protein acetylation in the mitochondrial and non-mitochondrial compartments and in nuclear gene regulation. Aim 3: Test the hypothesis that NR improves mitochondrial function and reduces inflammatory response in HF patients. 1. Measure mitochondrial function in peripheral blood mononucleated cells (PBMC). 2. Determine the inflammatory response in PBMC from NR-treated vs. placebo participants. 3. Compare effects on the circulating inflammasome vs. myocardial inflammation.