Abstract Body (Do not enter title and authors here): Nicotinamide adenine dinucleotide (NAD+) is crucial for life, as it is required as a redox cofactor or substrate for hundreds of enzymes. Notably, the NAD⁺ pool decreases in many rodent heart failure (HF) models as well as failing human hearts. High doses (~500mg/kg) of NAD⁺ precursors such as nicotinamide riboside (NR) have shown therapeutic potential in rodent models – rescuing almost all HF phenotypes. However, translating findings from preclinical models to humans is hindered as the tolerability of high doses remains uncertain, and the efficacy of lower doses considered safe in humans remains poorly explored. Swine have a more human-like cardiovascular system than do rodents and closely recapitulate many aspects of human HF after transient coronary artery occlusion. Thus, the swine HF model presents the opportunity to test the tolerability/toxicity of NR-high doses.

We hypothesize that NAD⁺ metabolism can be targeted to ameliorate functional capacity in failing hearts.

We induced myocardial infarction (MI) in the swine via 180 min percutaneous balloon occlusion of the LAD coronary artery with or without NR treatment (500mg/kg NR orally beginning 1 week prior to MI and throughout the study). Cardiac imaging studies, and blood work (CBC, RFT, and LFT) were conducted at weeks 2, 4, and 8 post-MI to ascertain cardiac function and overall health of the pigs. Blood, PBMCs, spleen, and myocardial NAD⁺ content were also assessed. Lastly, the cytokines IL-1β, 4, and 6 were tested.

We saw that supplementing a high dose of NR in the porcine MI model increased blood, PBMCs, spleen, and myocardial NAD⁺. Intriguingly, hearts of swine treated with 500mg/kg NR-treated showed preserved LVEF (49.68 ± 2.92) at the terminal time point of the study, in contrast to a significant (p=0.01) decrease in LVEF (36.10 ± 5.81) in the Ctrl pigs. Notably, LVEF showed strong associations with myocardial NAD⁺ content. Also, systolic function was sustained with the high-NR dose in the absence of adverse impacts on CBC, RFT, and LFT. Inflammatory cytokines IL-1β, 4, and 6 trended lower in NR-treated swine versus the controls.

Our data show for the first time that targeting NAD⁺ metabolism has translational potential for ameliorating HF phenotypes (human-like) in swine. High dose oral NR was well-tolerated in swine. Thus, our data support the need for further studies to explore the therapeutic potential of NAD⁺ precursors in HF prevention and treatment beyond rodent models.