 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/brand-header-logo.svg){kind=logo}
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Zeneng-Wang.jpg)
Zeneng WangPage 1
Nature Medicine | Volume 30 | February 2024 | 424–434 424nature medicineArticlehttps://doi.org/10.1038/s41591-023-02793-8Aterminalmetaboliteofniacinpromotesvascularinflammationandcontributestocardiovasculardisease riskDespite intensive preventive cardiovascular disease (CVD) efforts,substantial residual CVD risk remains even for individuals receiving allguideline-recommended interventions. Niacin is an essential micronutrientfortified in food staples, but its role in CVD is not well understood. In thisstudy, untargeted metabolomics analysis of fasting plasma from stablecardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422females) suggested that niacin metabolism was associated with incidentmajor adverse cardiovascular events (MACE). Serum levels of the terminalmetabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY)and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated withincreased 3-year MACE risk in two validation cohorts (US n = 2,331 total,n = 774 females; European n = 832 total, n = 249 females) (adjusted hazardratio (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 variantrs10496731, which was significantly associated with both 2PY and 4PYlevels, revealed an association of this variant with levels of solublevascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmedassociation of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075females, P = 3.6 × 10−18). Moreover, sVCAM-1 levels were significantlycorrelated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333females) (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 isomer2PY, induced expression of VCAM-1 and leukocyte adherence to vascularendothelium in mice. Collectively, these results indicate that the terminalbreakdown products of excess niacin, 2PY and 4PY, are both associatedwith residual CVD risk. They also suggest an inflammation-dependentmechanism underlying the clinical association between 4PY and MACE.Cardiovascular disease (CVD) is a leading cause of morbidity and mor-tality worldwide1, but only a portion of attributable risk is accountedfor by established risk factors2. Despite substantial advances in thera-pies, residual CVD risk remains high, suggesting that additional, yetunrecognized factors are involved in CVD. In randomized clinical trialsof proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,treatment groups achieved mean low-density lipoprotein (LDL) levelswell below 50 mg dl−1 but still had substantial cardiovascular eventReceived: 16 March 2023Accepted: 22 December 2023Published online: 19 February 2024Check for updates e-mail: hazens@ccf.orgA list of authors and their affiliations appears at the end of the paperContent courtesy of Springer Nature, terms of use apply. Rights reserved
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Pascal-Burger-3.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Aruna-Pradhan.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Jannick-Dorresteijn.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/author_default_m.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Ina-Nemet-2.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Prasenjit-Saha-7.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Yan-Yao-15.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/profile_default_m.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Elisabeth-Steinhagen-Thiessen.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Network-module-based-pathway-analysis-identifies-MACE-associated-pathways-containing_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Overview-of-vitamin-B3-metabolism-as-defined-in-the-Human-MetaFishNet-MFN-model-a_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Serum-metabolite-m-z1530656Da-produces-CID-spectrum-similar-to-a-mixture-of-synthetic_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Illustration-of-methods-development-to-selectively-monitor-and-quantify-serum-levels-of_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Verifying-the-MACE-associated-serum-analyte-with-m-z1530656Da-is-comprised-of-2PY-and_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Comparison-of-2PY-and-4PY-levels-in-US-and-European-Validation-Cohorts-a-b-Serum_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Sensitivity-analysis-of-2PY-and-4PY-association-with-MACE-in-the-merged-cohort-US-and_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Transcriptomic-analysis-of-human-endothelial-cells-exposed-to-2PY-or-4PY-a-Human_W640.jpg){kind=spacer}
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Niacin-is-an-essential-micronutrient-fortified-in-food-staples-beyond-dietary_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Identification-of-the-MACE-associated-metabolite-2PY-and-4PY-the-terminal-metabolites-of_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Niacin-metabolites-2PY-and-4PY-are-associated-with-increased-prospective-MACE-risk-in-two_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/The-NAD-synthesis-gene-ACMSD-is-associated-with-4PY-levels-and-vascular-inflammation-a_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/The-niacin-metabolite-4PY-enhances-VCAM-1-expression-and-leukocyte-adhesion-in-vivo-a-b_W640.jpg)
 A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk _ Request PDF_files/Niacin-metabolites-2PY-and-4PY-are-associated-with-increased-VCAM-1-expression-and_W640.jpg)