2024-02-21 10:04:55
Cardiovascular diseases are one of the leading causes of morbidity and mortality worldwide. After taking into account currently known risk factors, the residual risk of cardiovascular disease remains high, which suggests that other, as yet unknown, factors are involved, explained Marc Ferrell of the Cleveland Clinic in the United States and his co-authors.
Niacin, also known as vitamin B3 or nicotinic acid, is a micronutrient essential for the synthesis of nicotinamide adenine dinucleotide (NAD) involved in redox reactions. Adults need at least 15 mg per day to avoid niacin deficiency syndromes, such as pellagra.
In a prospective international cohort study, the authors used a non-targeted metabolomic approach, making it possible to analyze all the metabolites present in the blood. The goal was to search for new metabolites and new pathways that would be linked to this residual risk of cardiovascular disease.
This analysis was carried out on the plasma of 1,162 patients with stable coronary disease, taken in the fasting state during scheduled coronary angiography. Researchers identified an analyte of unknown structure, which was found to be the major unknown metabolite associated with an increased risk of major adverse cardiovascular events.
Chemical characterization studies showed that the unknown serum metabolite was a mixture of two isomers, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide ( 4PY), metabolites of excess niacin and NAD metabolism (the levels of these metabolites are high when “the niacin/NAD pool is in excess”, specify the researchers). The study “suggests that niacin metabolism may be associated with cardiovascular events,” the authors concluded.
Secondly, an analysis by liquid chromatography by dilution of stable isotopes, coupled with mass spectrometry, was carried out in order to individually quantify these two isotopes on two validation cohorts: an American one of 2,331 patients and a European one of 832 patients.
This analysis showed that people with higher circulating levels of 2PY and 4PY had a higher risk of cardiovascular events in both cohorts. For 2PY, the risk was increased by 64% in the American cohort and doubled in the European cohort. For 4PY, the risk was increased by 89% in the American cohort and almost doubled in the European cohort.
Additional analyzes were carried out by the authors to determine the genetic and mechanistic links between the metabolites and this increase in risk. Their studies suggest an inflammation-dependent mechanism; with the involvement of a soluble vascular adhesion molecule, sVCAM-1.
Vitamin B3 exists as an over-the-counter and commonly used food supplement. In view of their results, the authors raise the question of the possible risk of excessive consumption and, moreover, call into question the practice across the Atlantic of systematic supplementation of flour and cereals with this vitamin.
They also suggest that their results could explain what they call the “niacin paradox”: the observation that the reduction in LDL cholesterol induced by niacin is not associated with a reduction in cardiovascular risk.
(Nature Medicine, online publication of February 19)
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