nicotinamide-beta-riboside and Heart-Failure

BACKGROUNDWhile mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODSWe compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTSWe demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSIONThese findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.TRIAL REGISTRATIONClinicalTrials.gov NCT03727646.FUNDINGThis study was funded by the NIH, the University of Washington, and the American Heart Association.

Topics: Female; Heart Failure; Humans; Inflammation; Leukocytes, Mononuclear; Male; Mitochondria, Heart; Models, Cardiovascular; NAD; Niacinamide; Oxygen Consumption; Pyridinium Compounds

Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD. To explore possible alterations of NAD. We observed a 30% loss in levels of NAD. The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.

Topics: Acrylamides; AMP-Activated Protein Kinases; Animals; Cardiomyopathy, Dilated; Citric Acid; Cytokines; Dietary Supplements; Disease Models, Animal; Gene Expression Profiling; Heart Failure; Metabolome; Mice; Mice, Transgenic; Myocytes, Cardiac; NAD; Niacinamide; Nicotinamide Phosphoribosyltransferase; Phosphotransferases (Alcohol Group Acceptor); Piperidines; PPAR alpha; Pyridinium Compounds; Rats; Serum Response Factor

Topics: Animals; Cardiomyopathy, Dilated; Heart Failure; Mice; NAD; Niacinamide; Pyridinium Compounds