Home Medizin Eine Studie legt nahe, dass ein hoher Gehalt an Vitamin-B3-Abbauprodukten mit einem höheren Risiko für Sterblichkeit, Herzinfarkt und Schlaganfall verbunden ist

Eine Studie legt nahe, dass ein hoher Gehalt an Vitamin-B3-Abbauprodukten mit einem höheren Risiko für Sterblichkeit, Herzinfarkt und Schlaganfall verbunden ist

von NFI Redaktion

In a recent study published in Nature Medicine, researchers used an untargeted metabolomics technique to search for new compounds and signaling pathways that may contribute to the residual risk of cardiovascular diseases (CVD).


Study: A Niacin endmetabolite promotes vascular inflammation and contributes to the risk of cardiovascular diseases. Image credit: Dragana Gordic/Shutterstock.com










Study: A Niacin endmetabolite promotes vascular inflammation and contributes to the risk of cardiovascular diseases. Image credit: Dragana Gordic/Shutterstock.com

Background

Cardiovascular diseases are a global health issue, with only a small portion of the risk being associated with known risk factors. Despite breakthroughs in therapy, the risk of cardiovascular disease remains high, indicating the presence of additional unidentified variables.

Niacin, an essential vitamin found in staple foods, is critical in cardiovascular diseases. However, the treatment groups had mean LDL levels <50 mg/dl, but significant cardiovascular event rates. Individuals with high inflammatory markers have an increased risk of developing cardiovascular diseases. However, the intake of niacin through food has increased due to the consumption of processed foods and fast food, raising concerns about the effectiveness of therapeutic niacin in reducing CVD risk.

About the Study

In the present study, researchers used untargeted mass spectrometry technology to identify circulating small molecules that predict the risk of cardiovascular diseases without established risk factors.

The researchers investigated clinical, genetic, and mechanistic associations between the terminal breakdown products of excess niacin and the occurrence of severe adverse cardiac events (MACE). They performed untargeted metabolomics analyses on fasting plasma from stable heart patients in a prospective discovery cohort and from participants undergoing elective diagnostic heart evaluations.

The researchers postulated that the putative MACE-associated analyte with m/z values of 153 Da could be a combination of two co-eluting structural isomers: the N1-methyl-2-pyridone-5-carboxamide (or 2PY) metabolite and the N1-methyl-4-pyridone-3-carboxamide (or 4PY) metabolite. They chemically synthesized both metabolite standards and performed several chemical characterization tests.

The team used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to examine the relationship between structural isomer concentrations in circulation and the risk of new-onset severe cardiovascular events in two validation populations [United States (US) cohort of 2,331 individuals and the European cohort of 832 individuals]. They conducted a sensitivity analysis of the validation cohort data to account for confounding by known risk variables.

The researchers used a genome-wide association study (GWAS) approach and meta-analyses to investigate the genetic determinants of circulating 2PY and 4PY levels. They combined the study results of the US validation cohort with publicly available summary statistics for 2PY and 4PY levels from multi-ancestry datasets. They reduced Acmsd expression in vivo by injecting mice with a liver-tropic adeno-associated virus (AAV) expressing either a short hairpin RNA (shRNA) targeting Acmsd or a scrambled control shRNA to directly test the assumption that ACMSD influences 2PY and 4PY levels.

The researchers also used Mendelian randomization analysis (MR) to determine if genetically higher 2PY and 4PY levels are causally associated with CVD outcomes. They conducted in vitro and in vivo functional studies to investigate whether 2PY or 4PY would induce VCAM-1 expression on endothelial cells. They used in vivo methods to examine the immediate effects of 2PY or 4PY on arterial VCAM-1 expression and function.

Results

Niacin metabolites were associated with an increase in severe adverse CVD events (MACEs). Chemical production of authentic 2PY and 4PY standards and additional chemical characterization tests showed that the MACE-associated blood „analyte“ with m/z values of 153 Da was a combination of the co-eluting structural isomers 2PY and 4PY with the same elemental composition.

In the US and European validation cohorts, the serologic 2PY and 4PY levels were associated with an increased three-year risk of severe cardiovascular events[adjusted hazard ratios (HRs) for 2PY of 16 and 20; and for the 4PY metabolite: 19 and 20) Elevated 4PY levels were still strongly related to the incidence of major-type adverse cardiovascular event risk in both people with relatively maintained and compromised renal function.

An association-level study of the genetic variant rs10496731, strongly correlated with both metabolite levels, showed an association with soluble vascular cell adhesion molecule 1 (sVCAM-1). A meta-analysis revealed an association between rs10496731 and sVCAM-1 in 106,000 individuals, including 53,075 women. The validation group (974 individuals, 333 women) showed a significant correlation between sVCAM-1 expression and niacin metabolites.

The administration of the 4PY metabolite (but not 2PY) in physiological amounts increased VCAM-1 expression and leukocyte adhesion to vascular endothelial cells in murine animals. Both niacin metabolites were associated with the residual risk of cardiovascular diseases. The team also proposed an inflammation-dependent mechanism for the clinical association between the 4PY metabolite and severe adverse cardiovascular events.

The study results showed that two end metabolites of niacin and NAD metabolism, 2PY and 4PY, are independently associated with cardiovascular diseases, regardless of established risk factors. Both metabolites are genetically linked to vascular inflammation, with a gene variation strongly associated with circulating 2PY and 4PY levels, as well as sVCAM-1 levels. Excess niacin, particularly 4PY, is associated with an increased MACE risk and may contribute to the residual risk of cardiovascular diseases through inflammatory pathways. Further research is necessary to enhance understanding of these connections.

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