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A team at the Cleveland Clinic has identified a new contributor to cardiovascular disease: 4PY, a byproduct of excess niacin (vitamin B-3). Their research shows that high levels of 4PY are linked to an increased risk of heart attack, stroke, and vascular inflammation, which can lead to atherosclerosis.
Excess niacin fuels inflammation, cardiovascular disease through a newly discovered path.
Cleveland Clinic researchers have identified a new pathway that contributes to cardiovascular disease associated with elevated levels of niacin, a common B vitamin previously recommended for lowering cholesterol.
The team, led by Stanley Hazen, M.D., Ph.D., discovered a link between 4PY, a breakdown product of excess niacin, and heart disease. Higher circulating levels of 4PY were strongly associated with the development of heart attacks, strokes, and other adverse cardiac events in large-scale clinical studies. Researchers also demonstrated in preclinical studies that 4PY directly triggers vascular inflammation that damages blood vessels and can lead to atherosclerosis over time.
Implications for diagnostic and therapeutic approaches
The study, published on February 19 in Nature Medicine, It also details the genetic links between 4PY and vascular inflammation. The findings provide a basis for possible new interventions and therapies to reduce or prevent that inflammation.
“What’s interesting about these results is that this pathway appears to be a significant, but previously unrecognized, contributor to the development of cardiovascular disease,” said Dr. Hazen, chair of Cardiovascular and Metabolic Sciences at the Lerner Research Institute at the Cleveland Clinic and co-section chief of Preventive Cardiology at the Heart, Vascular and Thoracic Institute. “What’s more, we can measure it, which means there is potential for diagnostic testing. “This knowledge lays the foundation for developing new approaches that counteract the effects of this pathway.”
Reevaluation of Niacin Fortification and Use
Niacin (vitamin B-3) is very common in the Western diet. “For decades, the United States and more than 50 nations have mandated niacin fortification in staple foods such as flour, cereals, and oats to prevent diseases related to nutritional deficiency,” Dr. Hazen said. However, one in four subjects in the researchers’ patient cohorts appeared to be consuming too much and had high levels of 4PY, which appears to contribute to the development of cardiovascular disease.
Dr. Hazen compares our niacin intake to several faucets pouring water into a bucket. Once that bucket is full, it starts to overflow. The human body then needs to process that surplus and produce other metabolites, including 4PY.
“The bottom line is not that we should eliminate all of our niacin intake; that’s not a realistic approach,” Dr. Hazen said. “Given these findings, a debate over whether a continued mandate for niacin fortification of flours and cereals could be warranted in the United States.”
Cleveland Clinic researchers, led by Dr. Stanley Hazen, have identified a new pathway that contributes to cardiovascular diseases associated with elevated levels of niacin. Credit: Cleveland Clinic
Dr. Hazen notes that the broader use of over-the-counter supplements made with different forms of niacin has also become popular due to purported 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 fruits and vegetables while avoiding excess carbohydrates.
The new findings could also help explain why niacin is no longer a treatment of choice for lowering cholesterol. Niacin was one of the first treatments prescribed to reduce LDL or “bad” cholesterol. However, niacin ultimately proved to be less effective than other cholesterol-lowering medications and was associated with other negative effects and higher mortality rates in previous research.
“The effects of niacin have always been something of a paradox,” Dr. Hazen said. “Although niacin lowers cholesterol, the clinical benefits have always been less than expected based on the degree of LDL reduction. This led to the idea that excess niacin caused unclear adverse effects that partially offset the LDL-lowering benefits. We believe our findings help explain this paradox. This illustrates why it is so important to investigate residual cardiovascular risk; “We learn a lot more than we set out to find.”
The study authors note that long-term research is needed to evaluate the effect of chronic elevation of 4PY levels on atherosclerosis and other phenotypes.
The research is part of Dr. Hazen’s ongoing research into factors that contribute to residual cardiovascular risk. His team follows patients over time and collects blood samples to find chemical signatures that can predict the development of heart disease. He has made pioneering discoveries in atherosclerosis and inflammatory disease research, including the fundamental discovery linking gut microbial pathways to cardiovascular and metabolic diseases.
Reference: “A terminal metabolite of niacin promotes vascular inflammation and contributes to the risk of cardiovascular disease” February 19, 2024, Nature medicine.
DOI: 10.1038/s41591-023-02793-8
Dr. Hazen also directs the Center for Microbiome and Human Health at the Cleveland Clinic and holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis.
Marc Ferrell, former physician, Ph.D. A student in Dr. Hazen’s laboratory and a student in the Medical Scientist Training Program at Case Western Reserve University, he is the first author of the manuscript. The research reported in this publication was supported in part by the National Institutes of Health under award numbers R01HL103866, P01HL147823, R01HL133169, R01HL148110, R01HL168493 and U54HL170326.