Study suggests high levels of vitamin B3 breakdown products are linked to higher risk of mortality, heart attacks, and stroke

NewsGuard 100/100 Score

In a recent study published in Nature Medicine, researchers utilized an untargeted metabolomics technique to look for new compounds and pathways that may contribute to residual cardiovascular disease (CVD) risk.

Study: A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Image Credit: Dragana Gordic/Shutterstock.com
Study: A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Image Credit: Dragana Gordic/Shutterstock.com

Background

CVD is a worldwide health problem, with only a tiny proportion of the risk linked to known risk factors. Despite breakthroughs in therapeutics, the risk of CVD remains high, indicating the presence of other unidentified variables.

Niacin, an essential vitamin in dietary staples, is critical in CVD. Treatment groups had mean LDL levels <50 mg/dl but significant cardiovascular event rates. Individuals with high inflammatory markers have an increased chance of developing CVD. However, dietary niacin intake has increased due to the increasing consumption of processed and fast food, raising concerns regarding the efficiency of therapeutic niacin in lowering CVD risk.

About the study

In the present study, researchers used untargeted mass spectrometry technology to identify circulating small molecules that predict incident CVD event risks without established risk factors.

The researchers investigated clinical, genetic, and mechanistic links between the terminal breakdown products of excess niacin and the incidence of major adverse cardiac events (MACE). They conducted untargeted metabolomics analyses on fasting plasma from stable cardiac patients in a prospective discovery cohort and subjects with elective diagnostic cardiac examinations.

The researchers postulated that the putative MACE-related analyte with m/z values of 153 Da may be a combination of two co-eluted 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 conducted several chemical characterization tests.

The team used stable-isotope-dilution liquid chromatography with tandem mass spectrometry (LC-MS/MS) to examine the relationship between structural isomer levels in circulation and new-onset major-type adverse cardiovascular event risk in two validation populations [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 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 from the United States validation cohort with publicly available summary statistics for 2PY and 4PY levels from various 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 notion that ACMSD influences 2PY and 4PY levels.

The researchers also used Mendelian randomization (MR) analysis to determine if genetically higher 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 would induce VCAM-1 expression on endothelial cells. They used in vivo methods to investigate the immediate effects of 2PY or 4PY on arterial VCAM-1 expression and function.

Results

Niacin metabolites were associated with an increase in major adverse CVD events (MACEs). Chemical production of authentic 2PY and 4PY standards and additional chemical characterization tests demonstrated 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, serological 2PY and 4PY levels showed associations with increased three-year major-type adverse cardiovascular event risk [adjusted hazard ratios (HRs) for 2PY of 1.6 and 2.0, respectively; and for the 4PY metabolite: 1.9 and 2.0, respectively). Elevated 4PY levels were still strongly related to the incidence of major-type adverse cardiovascular event risk in both persons with relatively maintained and compromised renal function.

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

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

The study findings showed that two terminal metabolites of niacin and NAD metabolism, 2PY and 4PY, are associated with CVD regardless of established risk factors. Both metabolites genetically link to vascular inflammation, with a gene variation strongly associated with circulating 2PY and 4PY levels and sVCAM-1 levels. Excess niacin, particularly 4PY, is linked to increased MACE risks and may contribute to residual cardiovascular disease risk via inflammatory pathways. Further research is required to improve understanding of these relationships.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Sidharthan, Chinta. (2024, February 19). Study suggests high levels of vitamin B3 breakdown products are linked to higher risk of mortality, heart attacks, and stroke. News-Medical. Retrieved on April 16, 2024 from https://www.news-medical.net/news/20240219/Study-suggests-high-levels-of-vitamin-B3-breakdown-products-are-linked-to-higher-risk-of-mortality-heart-attacks-and-stroke.aspx.

  • MLA

    Sidharthan, Chinta. "Study suggests high levels of vitamin B3 breakdown products are linked to higher risk of mortality, heart attacks, and stroke". News-Medical. 16 April 2024. <https://www.news-medical.net/news/20240219/Study-suggests-high-levels-of-vitamin-B3-breakdown-products-are-linked-to-higher-risk-of-mortality-heart-attacks-and-stroke.aspx>.

  • Chicago

    Sidharthan, Chinta. "Study suggests high levels of vitamin B3 breakdown products are linked to higher risk of mortality, heart attacks, and stroke". News-Medical. https://www.news-medical.net/news/20240219/Study-suggests-high-levels-of-vitamin-B3-breakdown-products-are-linked-to-higher-risk-of-mortality-heart-attacks-and-stroke.aspx. (accessed April 16, 2024).

  • Harvard

    Sidharthan, Chinta. 2024. Study suggests high levels of vitamin B3 breakdown products are linked to higher risk of mortality, heart attacks, and stroke. News-Medical, viewed 16 April 2024, https://www.news-medical.net/news/20240219/Study-suggests-high-levels-of-vitamin-B3-breakdown-products-are-linked-to-higher-risk-of-mortality-heart-attacks-and-stroke.aspx.

Comments

  1. Mike Monahan Mike Monahan United States says:

    The universe of the study is heart patients.  The advice should logically apply only to heart patietnts. I'm not seeing what the hazard ratios of heart patients outside of the study were, as compared to those taking niacin.  In naming the metabolites as a cause, are there other metabolites not mentioned like NMN? What happens when NMN is no longer present in patients that have reduced niacin levels?  What are the hazards of low niacin as compared to high niacin? What is considered the correct dose of niacin in this study? There's so much that's not studied or understood that it's difficult to see anyone taking action on half baked science... until you realized that the beneficiary of not taking niacin to lower cholesterol is actually the pharmaceutical companies that sell cholesterol lowering drugs...whose side effects are never part of a published study...because to do such research essentially ruins your career.  But frankly we all know of the negative side effects of statins but we won't study those.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Integrating social determinants of health to enhance heart failure risk prediction