Research News

Cleveland Clinic researchers have identified a new pathway that contributes to cardiovascular disease that is associated with excess levels of niacin, a B-vitamin common in the American diet and previously recommended to lower cholesterol.

The team, led by Stanley Hazen, PhD, MD, discovered that a blood metabolite called 4PY is associated with development of heart attack, stroke and other adverse cardiac events. Higher circulating levels of 4PY were strongly associated with cardiovascular event risk in large scale clinical studies. 4PY is a breakdown product of excess niacin. In mechanistic studies, directly delivering 4PY led to vascular inflammation and cardiovascular disease in preclinical models. Chronic vascular inflammation underlies diseases like atherosclerosis, but more research is needed to figure out how to reduce or prevent that inflammation.

The study, published in Nature Medicine, also details genetic links between 4PY and vascular inflammation. The findings provide a foundation for new potential interventions and therapeutics to prevent or reverse this inflammation. 

Niacin spillover and 4PY 

Niacin is almost impossible to avoid. Since World War II and food rationing, niacin fortification has been mandated in flour, cereals and oats to prevent disease related to nutritional deficiency, Dr. Hazen says. Yet, 1 in 4 subjects appeared to be getting too much and had high levels of 4PY, which appears to contribute to cardiovascular disease development. Dr. Hazen notes broader use of supplements made with different forms of niacin (vitamin B-3) have also become more popular because of presumed anti-aging benefits.

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. Our bodies then need 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," says Dr. Hazen, though he recommends patients should still consult with their doctors before taking over-the-counter supplements.

"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. What's more, we can measure it, meaning potential for diagnostic testing. With recognition, we also now can work on targeting the pathway for therapeutics development."

Effects are clear – even without a microscope 

The results 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. 

First author Marc Ferrell, PhD, spent five years in Dr. Hazen's lab working on this research. He's currently finishing up his medical training as a student at Case Western Reserve University's Medical Scientist Training program. Despite observational studies in humans that suggested niacin was related to inflammation, it was still a surprise when preclinical studies so clearly revealed the association.

"It normally takes careful analysis under a microscope to see brighter staining for inflammatory markers in tissues – in this case the inflammation was obvious to the naked eye when we introduced 4PY," Dr. Ferrell says. "The results indicate our need for randomized, controlled trials to test supplements related to niacin to see if they increase these inflammatory markers. There are several ongoing trials that could collect that data now." 

The findings, Dr. Hazen says, help unravel the "paradox" around niacin's effects. Despite niacin lowering cholesterol, the clinical benefits have always been less than anticipated. This study supports the idea that niacin's unintended adverse effects may counteract the positive effects on LDL.

"Though it wasn't what we were expecting or searching for in our studies, this shows why investigating residual cardiovascular risk is so critical," Dr. Hazen added. "We learn so much more than what we set out to find." 

Dr. Hazen also directs Cleveland Clinic's Center for Microbiome & Human Health and the Department of Cardiovascular and Metabolic Sciences at the Lerner Research Institute. He also holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis.