Nicotinamide Riboside in Systolic Heart Failure

Mitochondrial dysfunction has been implicated in heart failure (HF), and is associated with an imbalance in intracellular ratio of reduced nicotinamide-adenine dinucleotide (NADH) to oxidized nicotinamide-adenine dinucleotide (NAD), or the NADH/NAD ratio. In mouse models of HF, we have found that normalization of the NADH/NAD, through supplementation with NAD+ precursors, is associated with improvement in cardiac function. This Study will randomize participants with systolic HF (ejection fraction ≤40%) to treatment with the NAD precursor, nicotinamide riboside (NR) or matching placebo, uptitrated to a final oral dose of 1000mg twice daily, to determine the safety and tolerability of NR in participants with systolic HF.

Aim 1: Determine the safety and tolerability of NR in patients with clinically stable, systolic heart failure (LVEF \<40%). To accomplish this Aim:

A) a total of 30 participants with clinically stable, systolic heart failure (LVEF \<40%) will undergo 2:1 randomization to NR 250mg PO twice daily or matching placebo B) NR (or matching placebo), will be increased weekly by 250mg/dose (500mg/day) to a final dose of 1000mg PO twice daily. Clinic visits with labs bi-weekly during dose escalation will assess HF symptoms and monitor labs \[B-type natriuretic peptide (BNP), complete blood count (CBC), glycosylated hemoglobin, alanine aminotransferase (ALT), creatine kinase (CK), insulin/glucose, uric acid, electrolytes, blood urea nitrogen (BUN) and creatinine (Cr).

C) to ensure intermediate-term safety and tolerability, participants will continue on their maximum tolerated dose (of NR or placebo) through Study Week 12

Aim 2: Determine whether, at the doses employed, NR and NAD are detectable in whole blood.

Aim 3 (Exploratory): Assess the range of potential effect sizes of NR on HF surrogate endpoints using:

A) Six-minute walk tests (6MWTs) at each visit (including Screening) to assess functional capacity B) Echocardiography at Baseline and Week 12 to assess LV systolic function (by real-time, 3D echocardiography) and diastolic function (by integrated Doppler and tissue Doppler imaging)

Eligibility Criteria:
Inclusion Criteria:

* Men and women aged 18 and older with systolic heart failure \[left ventricular ejection fraction (LVEF) by standard 2D echocardiography or radionuclide ventriculography of ≤40%\] deemed, in the clinical opinion of their treating cardiologist to be non-ischemic or ischemic in origin.
* Clinically stable (no cardiac procedures or hospitalizations for hospitalizations for cardiac causes, including HF, ischemia or arrhythmia) within the previous 3 months
* Ability to undergo study procedures, including scheduled visits, blood draws and six-minute walk test (6MWT)
* Willingness/ability to provide informed consent

Exclusion Criteria:

* Heart failure with preserved ejection fraction (LVEF greater than 40%)
* Heart failure due, in the opinion of their treating cardiologist, to etiologies other than non-ischemic or ischemic. Examples of exclusionary heart failure etiologies include primary valvular disease, or infiltrative or inflammatory cardiomyopathies.
* Cardiac surgery, percutaneous coronary intervention (PCI) or cardiac device implantation within the previous 3 months
* Hospitalizations for cardiovascular causes, including heart failure, chest pain, stroke, transient ischemic attack or arrhythmias within the previous 3 months
* Inability to perform Study visits or procedures (e.g., physical inability to perform 6MWT)
* Unwillingness/inability to provide informed consent
* ALT greater than 3 times the upper limit of normal, hepatic insufficiency or active liver disease
* Recent history of acute gout
* Chronic renal insufficiency with creatinine ≥2.5mg/dL
* Pregnant (or likely to become pregnant) women
* Significant co-morbidity likely to cause death in the 6 month follow-up period
* Significant active history of substance abuse within the previous 5 years
* Current participation in another long-term clinical trial
* History of intolerance to NR precursor compounds, including niacin or nicotinamide