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.
Excess Niacin Fuels Inflammation and Cardiovascular Disease Through Newly Discovered Pathway
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.
The study, published in Nature Medicine , 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 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 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 completely eliminate 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 US."
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. "Despite cholesterol lowering by niacin, 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 counteracted "We believe our findings help explain this paradox . This illustrates why it is so important to investigate residual cardiovascular risk ; we learn much 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.
Together, these results indicate that the terminal degradation products of excess niacin, 2PY and 4PY, are associated with residual risk of cardiovascular disease. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and major CV events.
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. student in Dr. Hazen’s laboratory and a student in the Medical Scientist Training Program at Case Western Reserve University, is the first author of the manuscript. The research presented in this publication was funded in part by the National Institutes of Health under award numbers R01HL103866, P01HL147823, R01HL133169, R01HL148110, R01HL168493, and U54HL170326.
