Nutrition, terminal NAD metabolites and cardiovascular disease - SUMMARY In this application, we used untargeted metabolomics as discovery platform to structurally identify and characterize an unknown metabolite whose levels in plasma in a Discovery Cohort are strongly associated with incident risk for development of cardiovascular disease (CVD), and major adverse cardiovascular events (MACE = myocardial infarction (MI), stroke or death). Extensive chemical structural elucidation efforts revealed the “analyte” was in fact a pair of rarely studied structural isomers that serve as terminal metabolites of NAD+ metabolism, namely 2PY and 4PY. Vitamin B3 is niacin (nicotinic acid, and nicotinamide), and is integrally linked to both NAD+ and cellular energy metabolism. This proposal integrates nutrition and metabolism data in both health and disease. It also explores mechanisms of micro-nutrient processing (NAD+/niacin) and its impact on metabolism, pathophysiological pathways and disease outcomes. Preliminary data indicate the terminal metabolite, 4PY, but not its structural isomer 2PY, is clinically associated with CVD risks, and preliminary cellular and disease model studies suggest 4PY directly fosters vascular inflammation and heightened thrombosis potential. We will use a variety of approaches to explore the metabolism, biology and (patho) physiological links between 4PY and CVD relevant phenotypes. Our studies also suggest that a specific genetic variant, coupled with dietary tryptophan, can give rise to both enhanced 4PY levels, and vascular endothelial cell activation, pro-inflammatory gene programs, and heightened atherosclerosis and thrombosis potential. The present studies have significant potential public health importance for many reasons. They identify a new potential contributor to residual CVD risks independent of traditional risk factors. They also call for reassessment of the safety of cereal fortification, a practice institutionalized in the US since WWII. Finally, the present studies may help explain the “niacin paradox” wherein large doses of niacin used to lower LDL cholesterol, failed to match expectations in clinical trials based on the degree of LDL lowering.
