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Cardiovascular disease (CVD) is disease of the heart and blood vessels. CVD is a leading cause of death in the United States for both men and women. Despite advances in prevention and treatment, it remains widespread. This suggests that there may be risk factors that are not yet recognized.
To investigate, an NIH-funded research team, led by Dr. Stanley Hazen at the Cleveland Clinic, searched for products of metabolism that might contribute to CVD risk. The results appeared in Nature Medicine on February 19, 2024.
The team analyzed blood plasma from more than 1,100 people for molecules associated with major adverse cardiac events, such as heart attacks and strokes. They identified two such molecules, 2PY and 4PY. Both of these are produced when the body breaks down excess niacin.
Niacin, also known as nicotinic acid or vitamin B3, is an essential part of the diet. Many countries require that staple foods like cereals, flour, oats, and grains be fortified with niacin to prevent deficiency. In the United States, niacin must be added to “enriched” foods. The recommended amount of niacin is 14–18 mg/day for adults.
High–dose niacin (1,500–2,000 mg/day) was also one of the first cholesterol-lowering drugs. But studies found that niacin, unlike newer cholesterol-lowering drugs, did not lower the risk of heart attack or stroke. Researchers hadn’t understood why.
The researchers examined 2PY and 4PY levels in two other groups, one American and one European, totaling more than 3,000 people. They confirmed that elevated levels of either molecule were associated with increased risk of major cardiac events. People with 2PY or 4PY levels in the top 25% had 1.6-2 times the risk of major cardiac events over the next three years as those with levels in the bottom 25%, even after controlling for other CVD risk factors.
Levels of both 2PY and 4PY were associated with variants in a gene called ACMSD. The team found that levels of another protein, called VCAM-1, were also associated with ACMSD variants. Furthermore, VCAM-1 levels correlated with 2PY and 4PY levels.
VCAM-1 is known to help white blood cells stick to the walls of blood vessels as part of the inflammatory response. This contributes to the formation of plaque in arteries. Injecting mice with 4PY, but not 2PY, increased the amount of VCAM-1 on the walls of blood vessels and the number of stuck white blood cells.
These findings suggest that excess niacin may be a risk factor for CVD. When excess niacin is broken down into 4PY, this breakdown product activates inflammatory pathways that are known to promote plaque formation in arteries. This may increase the risk of major cardiac events.
“Niacin’s effects have always been somewhat of a paradox,” Hazen says. “Despite niacin lowering cholesterol, the clinical benefits have always been less than anticipated based on the degree of LDL [cholesterol] 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.”
The study results could lead to better assessment of CVD risk. They also highlight the importance of further research on the health effects of supplemental niacin.
—by Brian Doctrow, Ph.D.