In the early 20th century, the deadliest nutrient-related disease in US history ravaged the American South. Pellagra, a disease caused by a deficiency in niacin and/or tryptophan, is marked by the four "D's": diarrhea, dermatitis that leads to gruesome skin plaques, dementia, and death. At its peak during the Great Depression, pellagra killed nearly 7,000 Southerners a year. Between 1906 and 1940, researchers estimate that the epidemic struck roughly 3 million Americans, killing around 100,000.
The deadly epidemic led to voluntary—and eventually mandatory—fortification of wheat and other cereals with niacin (aka Vitamin B3). By the middle of the century, pellagra nearly vanished from the US. But, decades later, the public health triumph may be backfiring. With Americans' diets more reliant than ever on processed, niacin-fortified foods, the average niacin intake in the US is now nearing what's considered the tolerable upper limit of the nutrient, according to a federal health survey. And an extensive study recently published in Nature Medicine suggests that those excess amounts of niacin may be exacerbating cardiovascular disease, increasing risks of heart attacks, strokes, and death.
The study, led by Stanley Hazen, chair of Cardiovascular and Metabolic Sciences at Cleveland Clinic's Lerner Research Institute, connected high blood levels of a breakdown product of niacin—and to a lesser extent, tryptophan—to an elevated risk of major adverse cardiovascular events (MACE). And this elevated risk appears to be independent of known risk factors for those events, such as high cholesterol.
"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," Hazen said in an announcement of the study. It can be measured, he added, and one day could be a new avenue for treatment and prevention.
Metabolite fishing
Hazen and his colleagues didn't start out suspecting niacin could be a culprit in cardiovascular disease. They arrived at that point after fishing through patients' blood plasma. The researchers were carefully inventorying metabolites in the fasting plasma of 1,162 patients who had been evaluated for cardiovascular disease. They were looking for anything that might be linked to a heightened risk of heart attack, stroke, or death in a three-year period that couldn't entirely be explained by other risk factors. Despite advances in identifying and treating cardiovascular disease, researchers have noted that some patients continue to be at risk of serious cardiovascular events despite having their traditional risk factors treated and controlled. Hazen and his colleagues wanted to know why.
The metabolomic trawling came up with an unknown metabolite (signature C7H9O2N2) that was significantly linked to having a MACE in the three-year period. People who had higher levels of this metabolite circulating in their systems were within the top 75th percentile for relative MACE risk in the cohort. Further work identified the metabolite as actually being two related molecules: 2PY (N1-methyl-2-pyridone-5-carboxamide) and 4PY (N1-methyl-4-pyridone -3-carboxamide)—both the final breakdown products of niacin.