Cleveland Clinic researchers have identified a new pathway that contributes to heart disease linked to high levels of niacin, a common B vitamin previously suggested to lower cholesterol.

The team, led by Stanley Hazen, MD, PhD, discovered a link between 4PY, a breakdown product from excess niacin, and heart disease. High circulating levels of 4PY were strongly associated with the development of heart attack, stroke, and other adverse cardiovascular events in large clinical studies. Researchers have also shown in clinical studies that 4PY directly stimulates vascular inflammation that damages blood vessels and can lead to atherosclerosis over time.

The study, published in The nature medicine, also details genetic links between 4PY and vascular inflammation. The findings provide a basis for potential new interventions and treatments to reduce or prevent this inflammation.

“What’s interesting about these findings is that this pathway is previously unrecognized in the development of cardiovascular disease,” said Dr. Hazen, chair and co-section chief of cardiovascular and metabolic sciences at the Lerner Research Institute at the Cleveland Clinic. appears to be a minor but important contributor.” Preventive Cardiology at the Heart, Vascular and Thoracic Institute. “What’s more, we can measure it, meaning that there is potential for diagnostic testing. These insights set the stage for developing new approaches to counteract the effects of this pathway.”

Niacin (vitamin B-3) is very common in the Western diet. “For decades, the United States and more than 50 countries have mandated niacin fortification in staple foods such as flour, grains and oats to prevent malnutrition-related disease,” said Dr. Hazen. Yet one in four subjects in the researchers’ patient groups were overweight, and had high levels of 4PY, which has been shown 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 begins to expand. The human body then needs to process this spillover and produce other metabolites, including 4PY.

“The bottom line is not that we should eliminate our entire intake of niacin — that’s not a realistic approach,” Dr. Hazen said. “Given these results, the continued mandate of fortification of flour and cereals with niacin in the United States may be warranted.”

Dr. Hazen notes that the widespread use of over-the-counter supplements made with various forms of niacin has also become popular for its anti-aging purposes. He adds that patients should consult their doctors before taking over-the-counter supplements and should focus on eating a diet rich in fruits and vegetables while avoiding high carbohydrates.

The new findings may also help explain why niacin is no longer a cholesterol-lowering treatment. Niacin was one of the first treatments recommended to lower LDL or “bad” cholesterol. However, niacin ultimately proved to be less effective than other cholesterol-lowering drugs and was associated with other adverse effects and higher mortality rates in previous research.

“The effects of niacin have always been somewhat controversial,” Dr. Hazen said. “Despite niacin lowering cholesterol, the clinical benefits have always been less than expected based on the degree of LDL reduction. This has led to the idea that niacin excess causes unexplained adverse effects that are partially due to LDL reduction. We believe our findings help explain this discrepancy. It illustrates why investigating residual cardiovascular risk is so important; we learn more than we thought. Had to find out.”

Longer-term investigations are needed to assess the effect of chronically elevated 4PY levels on atherosclerosis and other phenotypes, the study authors note.

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 look for chemical signatures that can predict the development of heart disease. He has made important discoveries in atherosclerosis and inflammatory disease research, including seminal discoveries linking the gut microbial pathway to cardiovascular disease and metabolic diseases.

Dr. Hazen also directs the Cleveland Clinic’s Center for Microbiome and Human Health and holds the John Blaxma Chair in Vascular Cell Biology and Atherosclerosis.

Mark Farrell, a former MD, Ph.D. student in Dr. Hazen’s laboratory and a student in Case Western Reserve University’s Medical Scientist Training Program, is the first author of the manuscript. 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.