nicotinamide riboside in systolic heart failure

Conditions: Heart Failure, Systolic

Summary: 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

Keywords: nicotinamide riboside nicotinamide-adenine dinucleotide