Cardiovascular disease (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 (vitamin B3) is critical in CVD treatment but physicians in the past have speculated that niacin lacking could be a predisposing factor for CVD and/or heart failure. Niacin, indeed, is the structural precursor for NAD+, a redox cofactor for many enzymes and a cellular shield against free oxidant species. Oxidative stress, indeed, is a cellular hallmark for chronic heart failure and atherosclerosis as well. Historically, niacin has been administered to reduce blood triglyceriides and to improve fat/cholesterol metabolism in liver. Individuals with high inflammatory markers have an increased chance of developing CVD. However, dietary niacin intake has increased due to the diffusion of processed and fast food, raising concerns regarding the efficiency of therapeutic niacin in lowering CVD risk.
In a recent study published in Nature Medicine, researchers from the Cleveland Clinic utilized an untargeted metabolomics technique to look for new compounds and pathways that may contribute to residual CVD risk. 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 also showed in preclinical studies that 4PY directly triggers vascular inflammation which damages blood vessels and can lead to atherosclerosis over time. Scientists 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) and the N1-methyl-4-pyridone-3-carboxamide (or 4PY). They chemically synthesized both metabolite standards and conducted several chemical characterization tests. The researchers also used Mendelian randomization (MER) 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. Niacin metabolites were associated with an increase in major adverse CVD events (MACEs). In the US and European validation cohorts, serological 2PY and 4PY levels showed associations with increased three-year major-type adverse cardiovascular event risk).
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. Only 4PY 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 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. Senior leader Dr. Hazen notes broader use of over-the-counter supplements made with different forms of niacin have also become popular because of presumed anti-aging purposes. He adds that patients should consult with their doctors before taking over-the-counter supplements and focus on a diet rich in fruit and vegetables while avoiding excess carbohydrates. The new findings also might help explain why niacin is no longer a go-to treatment for lowering triglycerides.
Niacin was also one of the first treatments prescribed to lower LDL or “bad” cholesterol. However, eventually niacin showed to be less effective than other cholesterol-lowering drugs like statins. These need milligrams of active principle (20 or 40mg at best), while niacin and/or nicotinic acid were administered starting form 250mg up to 1 gram daily to lower blood lipids. Not casually, the most relevat toxic side effects of niacin registered have been always on liver (cholestasis, high transaminases, etc.). In addition, nicotinamide was one of the first competitive inhibitors used in the laboratory to study the enzyme poly-ADP-ribose polymerase (PARP-1), which is involved in mechanisms of genomic surveillance, DNA repair and cooperation with other nuclear proteins that regulate gene expression (transcription factors). Pharmacological doses of this substance at the dosages mentioned can easily reach concentrations in the millimolar range sufficient to exert these molecular effects.
Furthermore, the effect can also manifest itself on the enzymatic counterpart of mitochondria, the mono-ADP-ribose transferases (mADPRTs), which use NAD to regulate mitochondrial transport and covalently modify resident enzymes to regulate their function. This could be an important mechanism of toxicity for the heart, since mitochondria are severely impaired in chronic heart failure to produce regular amounts of energy. Nicotinamide can also interfere with the action of sirtuins, especially form 1 (SIRT-1), which play a role in a wide variety of important biological processes, including transcriptional silencing, DNA repair, apoptosis, fat mobilization and aging. Among sirtuins, SIRT3 and SIRT5 reside in the mitochondrial matrix, and enhance the activity of enzymes involved in the Krebs cycle and oxidative phosphorylation metabolism, which is me main aspect of cellular energy imbalance in patients with chronic heart failure.
There is certainly still a lot of information to gain from this type of research, but having the awareness that not all aspects of human metabolism are not known can help to reveal events like this, in which using a vitamin as a drug can give unwanted surprises in the long term.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Ferrell M, Wang Z et al. Nature Med 2024 Feb; 30(2):424-434.
Yoshimura N et al. Clin Exp Nephrol. 2023 Nov; 27(11):901-911.
Deen CPJ, Veen AV et al. Nutrients. 2020 Jul 10; 12(7):2059.
Mericskay M. Archives Cardiovasc Dis. 2016; 109(3):207-215.