Nicotinamide Riboside in LVAD Recipients
Condition: Heart Failure，Congestive; Heart Failure New York Heart Association Class IV; Mitochondrial Alteration
MeSH terms: Heart Failure
Study type: Interventional
Phase: Early Phase 1

Summary: 
      While preliminary data show that oral nicotinamide riboside (NR) supplementation increases
      myocardial levels of oxidized nicotine-adenine dinucleotide (NAD+) levels in mice, there has
      been no direct evidence that suggests oral NR increases NAD+ levels or improves mitochondrial
      function in human hearts. This Pilot Study is designed to obtain feasibility data for a
      planned, larger study testing the hypothesis that oral NR supplementation will increase
      myocardial NAD+ levels and improve cardiomyocyte mitochondrial function in participants with
      advanced heart failure planned for elective left ventricular assist device (LVAD)
      implantation. To demonstrate safety and feasibility of NR in this patient population, the
      investigators propose to enroll 5 participants planned for LVAD implantation in a Pilot Study
      of NR in which participants will receive NR, up-titrated over 3 days to a final NR dose of
      1000mg twice daily. Blood and myocardial tissue analyses collected previously from age- and
      gender-matched LVAD recipients will serve as controls.
    

Detailed description: 
      This Pilot Study will examine the following Aims:

      Aim 1: Enroll 5 participants scheduled for elective left ventricular assist device (LVAD)
      placement into an open-label study of nicotinamide riboside (NR).

      a. Participants will have labs (including safety panels) drawn at baseline (Day 1), then
      receive escalating doses of NR to a maximum dose of 1000mg twice daily by Day 3. Participants
      will be continued on NR at 1000mg twice daily until LVAD implantation surgery.

      On the morning of LVAD implantation Surgery (Day 5 or later), participants will have final
      labs drawn. Samples of fresh cardiac tissue removed from the left ventricular apex during
      LVAD implantation surgery will be collected in the operating room. The primary analyses will
      be performed on NR-treated participants who were on the maximum NR dose of 1000mg twice daily
      for at least 2 days prior to LVAD implantation surgery. The maximum duration of NR
      administration will be capped at 14 days. If the surgery doesn't happen by then, the
      participant will be withdrawn from the study.

      Aim 2: Determine the effect of NR (as compared to historical controls) on levels of the
      oxidized and reduced forms of nicotine-adenine dinucleotide (NAD+ and NADH, respectively),
      mitochondrial function and its regulation through modifications of the epigenome 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, respectively,
           electron microscopy (EM) and isolated mitochondria.

        3. Determine protein acetylation in the mitochondrial and non-mitochondrial compartments
           and changes in nuclear gene regulation.

      Aim 3: Test the hypothesis that NR improves mitochondrial function and reduces inflammatory
      response in heart failure (HF) patients receiving NR (as compared to historical controls).

        1. Measure mitochondrial function in peripheral blood mononucleated cells (PBMC).

        2. Determine the inflammatory response in PBMC.

        3. Compare effects on the circulating inflammasome vs. myocardial inflammation.
    

Intervention name(s): Nicotinamide riboside
Intervention type(s): Dietary Supplement
Intervention description(s): nicotinamide riboside supplied as 250mg capsules
Intervention MeSH terms: Niacinamide; Niacin; Nicotinic Acids
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: This single-center, open-label study will compare blood and myocardial NAD+ levels and other mitochondrial endpoints in participants with end-stage heart failure treated with open-label nicotinamide riboside prior to LVAD implantation to similar endpoints from untreated patients previously undergoing LVAD implantation.
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment