Circulating and vascular NAD+ metabolism remodeling in Tgαq*44 mice with progressive heart failure.

Heart failure (HF) is a complex systemic syndrome in which ongoing myocardial dysfunction and vascular alterations interact to drive disease progression. Given its pivotal role in cellular energetics and redox balance, nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cardiovascular homeostasis. We recently demonstrated that myocardial NAD+ depletion occurs early in Tgαq*44 mice, a model of chronic HF. Accordingly, this study sought to characterize systemic and vascular alterations in NAD+ metabolism throughout the progression of HF by profiling circulating NAD+ precursors and metabolites, and assessing vascular NAD+ catabolic pattern. In female Tgαq*44 mice aged 4-14 months, whole-blood NAD+ and serum nicotinamide (NAM) levels progressively declined with increasing HF severity and were strongly associated with deteriorating systolic function. Reduced circulating NAD+ availability coincided with enhanced aortic NAD+ turnover and increased aortic CD38 abundance in end-stage HF. In addition, we identified a low-molecular-weight VCAM-1-immunoreactive band in the aorta, consistent with enhanced vascular activation in Tgαq*44 mice. Advanced HF was also associated with perturbations in arginine-citrulline metabolism, characterized by elevated levels of methylated arginine derivatives that may compromise nitric oxide (NO) bioavailability. This was paralleled by progressive accumulation of 4-pyridone-3-carboxamide ribonucleoside (4PYR), an NAD+-derived endothelial toxin, whose levels correlated with all three methylarginines, suggesting convergent pathways of endothelial dysfunction. Collectively, these findings suggest that enhanced vascular NAD+ catabolism, associated with increased CD38 abundance, constitutes a previously unrecognized metabolic feature of HF progression that may contribute to systemic NAD+ dysregulation and endothelial dysfunction.