In a recent study published in natural medicineResearchers used untargeted metabolomics techniques to search for new compounds and pathways that may contribute to residual cardiovascular disease (CVD) risk.

background

CVD is a global health problem, but only a small portion of the risks are associated with known risk factors. Despite therapeutic breakthroughs, the risk of CVD remains high, indicating the presence of other unidentified variables.

Niacin is an essential vitamin found in staple foods and is important in CVD. Although the mean LDL level in the treatment group was less than 50 mg/dl, the cardiovascular event rate was significant. People with high inflammatory markers are more likely to develop CVD. However, increased consumption of processed and fast foods has increased dietary intake of niacin, raising concerns about the effectiveness of therapeutic niacin in reducing CVD risk.

About research

In this study, researchers used untargeted mass spectrometry techniques to identify circulating small molecules that predict risk of CVD events without established risk factors.

Researchers investigated the clinical, genetic, and mechanistic associations between excess niacin final breakdown products and the incidence of major adverse cardiac events (MACE). They performed an untargeted metabolomics analysis on fasting plasma from a prospective discovery cohort of stable cardiac patients and subjects who underwent elective diagnostic cardiac testing.

The researchers found that the putative MACE-associated analyte with an m/z value of 153 Da is a combination of two coeluted structural isomers, the N1-methyl-2-pyridone-5-carboxamide (or 2PY) metabolite and N1. I hypothesized that it could be. -Methyl-4-pyridone-3-carboxamide (or 4PY) metabolite. They chemically synthesized both metabolite standards and performed several chemical characterization tests.

The research team used stable isotope dilution liquid chromatography and tandem mass spectrometry (LC-MS/MS) to determine circulating structural isomer levels and new-onset major cardiovascular adverse events in two study populations. We investigated the relationship with event risk. [United States (US) cohort of 2,331 individuals and the European cohort of 832 individuals]. They performed a sensitivity analysis on validation cohort data to account for confounding with known risk variables.

The researchers investigated the genetic determinants of circulating 2PY and 4PY levels using a genome-wide association study (GWAS) approach and meta-analysis. They combined study results from a US validation cohort with publicly available summary statistics of his 2PY and 4PY levels from various multi-ancestry datasets. They reduced Acmsd expression in vivo by injecting mice with liver-tropic adeno-associated virus (AAV) expressing either short hairpin RNA (shRNA) targeting Acmsd or a scrambled control shRNA; We directly verified the concept that ACMSD affects 2PY and 4PY levels.

The researchers also used Mendelian randomization (MR) analysis to determine whether genetically high 2PY and 4PY levels were causally associated with CVD outcomes. They conducted in vitro and in vivo functional studies to investigate whether 2PY or 4PY induces VCAM-1 expression on endothelial cells.they used alive Methods to investigate the immediate effects of 2PY or 4PY on arterial VCAM-1 expression and function.

result

Niacin metabolites were associated with increased major adverse CVD events (MACE). Through chemical production of authentic 2PY and 4PY standards and additional chemical characterization testing, the MACE-related blood “analyte” with an m/z value of 153 Da is a co-eluting structural isomer of 2PY and 4PY with the same elemental composition. The combination has been proven.

In US and European validation cohorts, serological 2PY and 4PY levels were associated with increased risk of major types of adverse cardiovascular events over 3 years[adjustedhazardratios(HRs)for2PYof16and204PYmetabolites:19and20respectively)Elevated4PYlevelsremainedstronglyassociatedwiththeincidenceofriskofmajoradversecardiovasculareventsinboththosewithrelativelypreservedrenalfunctionandthosewithdecreasedrenalfunction[adjustedhazardratios(HRs)for2PYof16and20respectively;andforthe4PYmetabolite:19and20respectively)Elevated4PYlevelswerestillstronglyrelatedtotheincidenceofmajor-typeadversecardiovasculareventriskinbothpersonswithrelativelymaintainedandcompromisedrenalfunction[2PYの調整後ハザード比(HR)はそれぞれ16および20。4PY代謝物:それぞれ19と20)。4PYレベルの上昇は、腎機能が比較的維持されている人と腎機能が低下している人の両方において、依然として重大な心血管有害事象のリスクの発生率と強く関連していました。[adjustedhazardratios(HRs)for2PYof16and20respectively;andforthe4PYmetabolite:19and20respectively)Elevated4PYlevelswerestillstronglyrelatedtotheincidenceofmajor-typeadversecardiovasculareventriskinbothpersonswithrelativelymaintainedandcompromisedrenalfunction

Phenome-level association studies of the rs10496731 gene variation, which strongly correlated with the levels of both metabolites, found an association with soluble vascular adhesion molecule 1 (sVCAM-1). A meta-analysis found an association between rs10496731 and sVCAM-1 in 106,000 people, including 53,075 women. The validation group (974 individuals, 333 women) showed a significant correlation between sVCAM-1 expression and niacin metabolites.

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

Study results showed that two terminal metabolites of niacin and NAD metabolism, 2PY and 4PY, were associated with CVD independent of established risk factors. Both metabolites are genetically associated with vascular inflammation, and genetic variations are strongly associated with circulating 2PY and 4PY levels and sVCAM-1 levels. Excess niacin, particularly 4PY, is associated with increased MACE risk and may contribute to residual cardiovascular disease risk through inflammatory pathways. Further research is needed to better understand these relationships.