Products Cited in Publications Worldwide A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk

A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk

Marc Ferrell; Zeneng Wang; James T. Anderson; Xinmin S. Li; Marco Witkowski; Joseph A. DiDonato; James R. Hilser; Jaana A. Hartiala; Arash Haghikia; Tomas Cajka; Oliver Fiehn; Naseer Sangwan; Ilja Demuth; Maximilian König; Elisabeth Steinhagen-Thiessen; Ulf Landmesser; W. H. Wilson Tang; Hooman Allayee; Stanley L. Hazen

DOI:

Abstract

Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess , and , were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10–2.42) and 2.02 (1.29–3.18), respectively; for 4PY: 1.89 (1.26–2.84) and 1.99 (1.26–3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both and levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10−18). Moreover, sVCAM-1 levels were significantly correlated with both and in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10−5; 4PY: rho = 0.18, P = 1.1 × 10−8). Lastly, treatment with physiological levels of , but not its structural isomer , induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess , and , are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between and MACE.

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