Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

Preliminary animal studies by ourselves and others suggest that the dietary supplement, nicotinamide riboside (NR), may improve cardiac function in heart failure (HF) by increasing cellular levels of its metabolite, nicotinamide adenine dinucleotide (NAD+, NADH). This Study will address a key gap in current knowledge by assessing the mechanisms through which raising blood and myocardial NAD+ levels in humans mediates changes in mitochondrial function, protein and epigenetic modifications, as well as inflammation. Human myocardium will be obtained after 4-14 days of oral NR supplementation from advanced heart failure patients undergoing elective left ventricular assist device (LVAD) implantation. Positive results would provide evidence to proceed with further studies of NR as a mitochondria-targeted metabolic therapy in 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.

Inclusion Criteria:

1. End-stage heart failure due to ischemic or non-ischemic cardiomyopathy

   a. If implanted for destination therapy indication, must have New Your Heart Association (NYHA) Class IV Heart Failure AND left ventricular ejection fraction (LVEF) <25% OR maximum minute consumption of oxygen (VO2) <14 OR on requirement for continuous intravenous inotropes

2. Meet clinical and socioeconomic screening criteria for elective LVAD implantation by the University of Washington Mechanical Circulatory Support Program

3. Scheduled (or soon to be scheduled) for elective LVAD implantation

4. Age >18 years

Exclusion Criteria:

1. End-stage heart failure due to causes other than ischemic or non-ischemic cardiomyopathy (e.g., valvular, hypertrophic or infiltrative cardiomyopathies).

2. Disease that disqualifies from consideration for LVAD implantation by the University of Washington program:

   1. Cirrhosis as evidenced by liver biopsy
   2. Irreversible, severe renal disease (estimated glomerular filtration rate (eGFR) <30) or on chronic dialysis
   3. Untreated thyroid disease (hyper- or hypo-thyroidism)
   4. Severe complications of diabetes, such as diabetes-related amputation, severe retinopathy, peripheral neuropathy or diabetic renal disease (eGFR <30)

3. Tissue physiology or other factors that, in the opinion of the Cardiac Surgeons, make the patient at unacceptably high risk for adverse outcomes.

4. Non-compliance with current treatments, including failure to follow prescribed therapies, such as medications, clinic visits, diagnostic testing and behavioral contracts

5. Active use/abuse of illicit substances

6. Lack of adequate caregiver support to help patient manage LVAD

7. Known allergies to niacin, nicotinamide or warfarin

8. Inability to perform Study visits or procedures

9. Unwillingness/inability to provide informed consent.

10. Participants considered by the attending cardiologist and/or the investigator to be unsuitable for the study