Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin 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 niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), 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 2PY and 4PY 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 2PY and 4PY 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 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.

Berlin Institute of Health Berlin Germany

Berlin Institute of Health Center for Regenerative Therapies Berlin Germany

Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Department of Biochemistry and Molecular Medicine Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Cardiology Angiology and Intensive Care Deutsches Herzzentrum der Charité Campus Benjamin Franklin Berlin Germany

Department of Cardiovascular and Metabolic Sciences Lerner Research Institute Cleveland Clinic Cleveland OH USA

Department of Cardiovascular Medicine Heart Vascular and Thoracic Institute Cleveland Clinic Cleveland OH USA

Department of Endocrinology and Metabolism Charité Universitätsmedizin Berlin Berlin Germany

Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles CA USA

Friede Springer Cardiovascular Prevention Center at Charité Berlin Germany

German Center for Cardiovascular Research Partner Site Berlin Berlin Germany

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Systems Biology and Bioinformatics Program Department of Nutrition Case Western Reserve University Cleveland OH USA

West Coast Metabolomics Center University of California Davis Davis CA USA

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