A team from 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 diseaseCardiovascular disease refers to a group of conditions that affect the heart and blood vessels, such as coronary artery disease, heart failure, arrhythmias, and stroke. It is caused by a variety of factors, including lifestyle choices (such as smoking and poor diet), genetics, and underlying medical conditions (such as high blood pressure and diabetes). Cardiovascular disease is a leading cause of death worldwide, but can often be prevented or managed through lifestyle changes, medications, and medical procedures such as bypass surgery and angioplasty.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>cardiovascular disease through newly discovered pathway.
Cleveland Clinic researchers have identified a new pathway that contributes to cardiovascular disease associated with high levels of niacin, a common B vitamin previously recommended to lower cholesterol.
The team, led by Stanley Hazen, M.D., Ph.D., discovered a link between 4PY, a breakdown product from excess niacin, and heart disease. Higher circulating levels of 4PY were strongly associated with development of heart attack, stroke and other adverse cardiac events in large-scale clinical studies. The researchers also showed in preclinical studies that 4PY directly triggers vascular inflammation which 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, also details genetic links between 4PY and vascular inflammation. The findings provide a foundation for potential new interventions and therapeutics to reduce or prevent that inflammation.
“What’s exciting about these results is that this pathway appears to be a previously unrecognized yet significant contributor to the development of cardiovascular disease,” said Dr. Hazen, Chair of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute and Co-Section Head of Preventive Cardiology in the Heart, Vascular & Thoracic Institute. “What’s more, we can measure it, meaning there is potential for diagnostic testing. These insights set the stage for developing new approaches to counteract the effects of this pathway.”
Reevaluating Niacin Fortification and Use
Niacin (vitamin B-3) is very common in a 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 disease related to nutritional deficiency,” said Dr. Hazen. Yet one in four subjects in the researchers’ patient cohorts appear to be getting too much, and had high levels of 4PY, which appears to contribute to cardiovascular disease development.
Dr. Hazen compares our intake of niacin as multiple taps pouring water into a bucket. Once that bucket is filled, it begins to spill over. The human body then needs to process that spill-over and produce other metabolites, including 4PY.
“The main takeaway is not that we should cut out our entire intake of niacin – that’s not a realistic approach,” said Dr. Hazen. “Given these findings, a discussion over whether a continued mandate of flour and cereal fortification with niacin in the U.S. could be warranted.”
Cleveland Clinic researchers, led by Dr. Stanley Hazen, have identified a new pathway that contributes to cardiovascular disease associated with high levels of niacin. Credit: Cleveland Clinic
Dr. Hazen notes broader use of over-the-counter supplements made with different forms of niacin has 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 cholesterol. Niacin was 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 and was associated with other negative effects and higher mortality rates in previous research.
“Niacin’s effects have always been somewhat of a paradox,” Dr. Hazen said. “Despite niacin lowering of cholesterol, the clinical benefits have always been less than anticipated based on the degree of LDL reduction. This led to the idea that excess niacin caused unclear adverse effects that partially counteracted the benefits of LDL lowering. We believe our findings help explain this paradox. This illustrates why investigating residual cardiovascular risk is so critical; we learn so much more than what we set out to find.”
The study authors note that long-term investigations are needed to assess the effect of chronic elevation of 4PY levels on atherosclerosis and other phenotypes.
The research is part of Dr. Hazen’s ongoing investigation 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 seminal discovery linking gut microbial pathways to cardiovascular disease and metabolic diseases.
Reference: “A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk” 19 February 2024, Nature Medicine.
DOI: 10.1038/s41591-023-02793-8
Dr. Hazen also directs Cleveland Clinic’s Center for Microbiome and Human Health and holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis.
Marc Ferrell, a former M.D., Ph.D. student in Dr. Hazen’s laboratory and student in Case Western Reserve University’s Medical Scientist Training Program, is first author of the manuscript. Research reported in this publication was supported in part by the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health under award numbers R01HL103866, P01HL147823, R01HL133169, R01HL148110, R01HL168493, and U54HL170326.
Source: SciTechDaily
