Abstract Body (Do not enter title and authors here): Nicotinamide adenine dinucleotide (NAD⁺) is essential for cellular functions due to its roles as a redox cofactor or substrate for many enzymes. Intriguingly, the NAD⁺ pool declines in failing human hearts. Treatments with NAD⁺ precursors such as nicotinamide and nicotinamide riboside (NR) are shown to ameliorate cardiac dysfunction, hypertrophy, and metabolic dysregulation in several mouse models of heart failure. However, testing the therapeutic potential of NAD⁺ precursors in the combined transverse aortic constriction (TAC) and myocardial infarction (MI) model, representing both hypertension and ischemic insult, the two most common synergistic etiologies for myocardial dysfunction, remains unexplored. Hence, we investigated the potency of NR in preserving the structural and functional capacity of the heart in the TAC/MI model, recapitulating aspects of hypertension-induced cardiac hypertrophy and ischemic heart disease phenotypes.

We hypothesize that boosting NAD⁺ metabolism via NR supplementation will mitigate the cardiac remodeling in the TAC/MI hearts, thus ameliorating cardiac dysfunctions.

We induced cardiac pressure overload and MI by TAC and ligation of the apical portion of the LAD, respectively. NR (~500mg/kg/day) and saline treatments were initiated 24 hr post-TAC/MI and Sham surgeries. Cardiac imaging was done 4 weeks after treatment to assess cardiac systolic function and morphometrics. Also, cytokine assay was performed to ascertain the levels of pro-fibrotic TGF-β.

TAC/MI mice hearts showed significant (p=0.01) LVEF (38.86 ± 6.382) reduction compared to the LVEF (46.50 ± 7.871) those treated with NR (TAC/MI+NR). Comparing these LVEF with the Sham LVEF (58.01 ± 4.940) shows NR treatment mitigated the reduction of systolic function post-TAC/MI. Similarly, morphometric data showed that NR prevented hypertrophy of the LVPW compared with saline treatment (p=0.008), which was consistent with HW/BW significantly (p=0.007) decreased in TAC/MI+NR compared to TAC/MI mice. TGF-β2, a prototypic pro-fibrotic cytokine central to fibrotic remodeling was overtly elevated in TAC/MI (p<0.001) than TAC/MI+NR mice (p= 0.17) compared to the Sham mice.

Our data show for the first time that boosting the NAD⁺ pool with NR protects mice against systolic dysfunction and hypertrophy in TAC/MI mice, thus necessitating further studies to elucidate underlying mechanisms and facilitate translational potentials.