B75-32 Strategic Preterm Infant Metabolic Reprogramming Rescues Adult Cardio-Pulmonary Dysfunction

Rationale

Advances in neonatal care have increased survival in premature infants, but adult survivors demonstrate heightened risks of diminished lung function and signs of pulmonary hypertension. NAD+ deficiency in preterm infants is associated with adverse outcomes, yet whether early-life insufficiency in NAD+ mechanistically programs persistent cardiopulmonary dysfunction is unknown. We hypothesized that augmenting the availability of NAD+ precursor during the vulnerable neonatal period mitigates hyperoxia-induced bioenergetic stress, endothelial dysfunction, and later cardio-pulmonary dysfunction.

Methodology

The NAD+ precursor nicotinamide (NAM) was administered to lactating dams in drinking water from day of life (DOL) 0-10, (stopped at DOL10) in a hyperoxia murine model of prematurity with neonatal hyperoxia (85% oxygen, DOL 0-8) thereby delivering NAM to pups via maternal milk during hyperoxia and early recovery. Lung metabolomics, milk clot mass spectrometry, lung oxidative stress and autophagy markers at DOL10. At 6-7 months, pulmonary function testing, RV hypertrophy, and oxidative stress were assessed. In vitro, NAM was tested for its ability to rescue hyperoxia (85%)-induced impairments in human endothelial colony forming cell (ECFC) angiogenesis, oxidative stress, and migration.

Results

Maternal dietary NAM supplementation increased milk clot NAM (p < 0.001) and niacin (p < 0.05) and increased lung NAM (p < 0.0001) and 1-MNA (p < 0.0001) at DOL10 hyperoxia pups as compared to hyperoxia vehicle control; lung NAD+ trended upward (p = 0.07). Neonatal lungs demonstrated improved redox balance, with increased superoxide dismutase (SOD) (p < 0.001) and lowered oxidized glutathione (p < 0.05), while alleviating increases in lung fibrosis mediator hydroxyproline (p = 0.17), proliferation (p < 0.001), and abnormal autophagy markers BECLIN1 (p < 0.001) as compared to hyperoxia vehicle (n = 6-12, 3-6M/3-6F). At 6-7 months, body weight and composition did not differ. Despite similar adult size, neonatal NAM rescued adult lung compliance (p < 0.001), resistance (p < 0.01), and elastance (p < 0.01) (n = 19/grp, 8F/11M), while rescuing right ventricular hypertrophy (Fulton Index, p < 0.001) (p < 0.001, n = 22-27/grp, 11F/11+M). Adult lung NAM to NAD+ converting enzyme NAMPT was increased (p < 0.05) as well as elevation in protective SOD (p < 0.01). No sex differences were observed. In ECFCs, NAM restored angiogenesis (p < 0.001), increased migration (p < 0.05), reduced reactive oxygen species (p < 0.001), and improved mitochondrial well-being (p < 0.001) in hyperoxia compared to hyperoxia control.

Conclusion

Time-limited neonatal NAM supplementation improved developmental redox balance, restrained early remodeling signals, rescued adult lung mechanics, and prevented RV hypertrophy while restoring endothelial function under hyperoxia. NAD+ precursor supplementation represents a clinically feasible candidate strategy with potential durable benefit for individuals born preterm.

This abstract is funded by: Heartland Nutrition Initiative