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In the early 20th century, the deadliest nutrient-related disease in American history ravaged the southern part of the country. Pellagra, a disease caused by a deficiency of niacin and/or tryptophanis marked by the four “D’s”: diarrhea, dermatitis that causes horrible skin plaques, dementia and death. At its peak during the Great Depression, pellagra killed almost 7,000 southerners a year. Between 1906 and 1940, researchers estimate that the epidemic hit approximately 3 million Americans, killing around 100,000.
The deadly epidemic led to the voluntary (and eventually mandatory) fortification of wheat and other grains with niacin (also known as vitamin B3). By mid-century, pellagra nearly disappeared from the United States. But decades later, the triumph of public health may prove counterproductive. With American diets relying more than ever on processed and niacin-fortified foods, average niacin intake in the U.S. is now approaching what is considered the tolerable upper limit for this nutrient, according to a study. federal health survey. and an extensive study recently published in Nature Medicine suggests that those excessive amounts of niacin may be exacerbating cardiovascular disease, increasing the risks of heart attacks, strokes and death.
The study, led by Stanley Hazen, chair of Cardiovascular and Metabolic Sciences at the Lerner Research Institute at the Cleveland Clinic, linked high blood levels of a breakdown product of niacin (and, to a lesser extent, tryptophan) with a elevated risk of major adverse cardiovascular events (MAZO). And this elevated risk appears to be independent of known risk factors for those events, such as high cholesterol.
“What is interesting about these results is that this pathway appears to be a significant, but previously unrecognized, contributor to the development of cardiovascular disease,” Hazen said in an announcement of the study. It can be measured, she added, and could one day be a new avenue for treatment and prevention.
metabolite fishing
Hazen and his colleagues did not initially suspect that niacin could be the culprit behind cardiovascular disease. They reached that point after fishing in 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 an increased risk of heart attack, stroke or death over a three-year period that couldn’t be fully explained by other risk factors. Despite advances in the identification and treatment of cardiovascular diseases, researchers have noted that some patients remain at risk for serious cardiovascular events even though their traditional risk factors are treated and controlled. Hazen and her colleagues wanted to know why.
Metabolomic screening yielded an unknown metabolite (signature C7h9oh2north2) that was significantly related to having a MACE in the three-year period. People who had higher levels of this metabolite circulating in their systems were within the upper 75th percentile of relative risk for MACE in the cohort. Later work identified that the metabolite was actually two related molecules: 2PY (N1-methyl-2-pyridone-5-carboxamide) and 4PY (N1-methyl-4-pyridone-3-carboxamide), both end products of degradation of the niacin.