The Effect of Nicotinamide Riboside on Skeletal Muscle Function in Heart Failure Subjects

As life expectancy increases and acute cardiac mortality decreases, the incidence of chronic
heart failure (HF) continues to rise, and despite this, conceptual advances in the treatment
of chronic heart failure have not increased substantially over last few decades. One
intracellular component of heart failure progression is mitochondrial bioenergetic
dysfunction. Although the mechanism underpinning this is not completely understood, recent
metabolomics data demonstrated an incomplete flux of metabolites through oxidative
phosphorylation (OX PHOS) in HF. In parallel, data has shown that hyperacetylation of
mitochondrial bioenergetic enzymes, with the concomitant blunting of enzymatic activity is
evident in HF. Putting these together, an emerging hypothesis implicates excessive
acetylation of mitochondrial proteins with the subsequent blunting of bioenergetic enzyme
function, as a mechanism underpinning incomplete flux through OX PHOS resulting in HF
progression.

In parallel with cardiac bioenergetic deficiency chronic HF subjects display disrupted
skeletal muscle OX PHOS, which is thought to contribute towards overall fatigue and reduced
exercise tolerance. Interestingly exercise training in HF subjects improves skeletal muscle
mitochondrial OX PHOS capacity and subject activity levels. Exercise training additionally
increases activity of the mitochondrial regulatory deacetylase sirtuin enzymes SIRT1 and
SIRT3, in parallel with improved skeletal muscle OX PHOS capacity. At the same time
HF-associated disruption in skeletal muscle metabolic function activates skeletal muscle
cytokine production. These inflammatory programs, in turn, are proposed to contribute towards
impaired functional capacity in HF. Interestingly, and mirroring improved OX PHOS following
exercise programs in HF studies, exercise training similarly reduces skeletal muscle
inflammatory effects.

Biochemical and bioenergetic consequences of impaired mitochondrial OX PHOS leads to
decreased NAD+ levels, which exacerbate mitochondrial dysfunction by inactivating the NAD+
dependent sirtuin enzymes. Experimental studies using NAD+ precursors to increase NAD+
production have been shown to normalize NADH/NAD+ ratios and activate Sirtuin enzymes,
resulting in enhanced OX PHOS with beneficial effects in numerous systems including skeletal
muscle and in the blunting of inflammation.

In this pilot study we will directly assess the effect of the NAD+ precursor, nicotinamide
riboside (NR) on skeletal muscle mitochondrial OX PHOS in HF subjects using: skeletal muscle
NMR spectroscopy assessment of the rate of high energy phosphate recovery in response to
submaximal exercise; assessment of the effect of NR on functional capacity using
cardiopulmonary exercise testing (CPET) to determine VO(2max) and anaerobic threshold;
evaluation of the NR effect on serum metabolomics at rest and in response to CPET; and by
measuring circulating cytokine levels pre- and post- NR administration. These studies would
enable a more comprehensive assessment of the role for NR supplementation on skeletal muscle
mitochondrial function in subjects with systolic HF

- INCLUSION CRITERIA:

Men and women between the ages of 18 and 75 years with NYHA Class II-III systolic heart
failure (LVEF by standard echocardiography or radionuclide ventriculography of less than or
equal to 45%) deemed 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, skeletal
muscle exercise NMR spectroscopy and CPET testing

Willingness/ability to provide informed consent

Must be DEERS eligible to be enrolled in a research protocol at WRNMMC

EXCLUSION CRITERIA:

Heart failure with preserved ejection fraction (LVEF greater than 45%)

Change in heart failure medications due to deterioration of function with the exception of
up- or down-titration of diuretic dose up to 100% of baseline dose.

Heart failure due 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/TIA
or arrhythmias within the previous 3 months

Inability to perform Study visits or procedures (e.g., physical inability to perform
exercise testing)

Unwillingness/inability to provide informed consent

ALT greater than x3 upper limit of normal, hepatic insufficiency or active liver disease

Recent history of acute gout

Chronic renal insufficiency with creatinine greater than 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 drug study

History of intolerance to NR precursor compounds, including niacin or nicotinamide

MRI incompatible hardware including pacemakers or ICD s

Study adherence concerns

Individuals with diabetes type 1 and 2 who use insulin

Women of child-bearing potential unwilling to use contraception or unwilling to practice
abstinence

Breastfeeding women unwilling to stop breastfeeding