E-cig, tobacco flavors disrupt endothelial cell function

Flavoring additives commonly found in e-cigarettes and tobacco products have a detrimental effect on endothelial function, according to results of a study published in Arteriosclerosis, Thrombosis, and Vascular Biology.

“Our work and prior research have provided evidence that flavorings induce toxicity in the lung and cardiovascular systems. Flavorings are also a driver of youth tobacco use and sustained tobacco use among smokers,” said lead study author Jessica L. Fetterman, PhD, assistant professor of medicine, Boston University School of Medicine, Boston, MA.

E-cigarettes are battery-powered devices that heat liquids—including tobacco-derived nicotine, flavoring, and other additives—to produce an inhaled aerosol. The flavorings widely used include nine chemicals: menthol (mint), acetylpyridine (burnt flavor), vanillin (vanilla), cinnamaldehyde (cinnamon), eugenol (clove), diacetyl (butter), dimethylpyrazine (strawberry), isoamyl acetate (banana), and eucalyptol (spicy cooling).

These flavors have been deemed safe for ingestion, but their effects on cardiovascular health remain unknown.

The American Heart Associations (AHA) has cautioned against the use of e-cigarettes, stressing that because they contain nicotine they are tobacco products that affect the body in the same way other tobacco products do. The AHA also called for strong, new regulations to prevent the access, sale, and marketing of e-cigarettes to youth, as well as conducting more research into these products’ impact on health.

Since 2003, when e-cigarettes were first marketed, their popularity has increased among both adults and youths, who seem to be drawn by the flavorings. E-cigarettes are used primarily by adults who are current or former cigarette smokers as an aid to reduce or stop smoking and to limit the harm from smoking.

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In younger people, the use of e-cigarettes is rising rapidly: a full 37% of high school students reported vaping an e-cigarette in 2015. Flavored products have served to promote experimentation and use in this population.

In their study, Dr. Fetterman and colleagues tested the chemical flavorings for their short-term effects on endothelial cells, which they collected from nine nonsmokers/non-e-cigarette users, six nonmenthol cigarette smokers, and six menthol cigarette smokers. 

In both groups of smokers, similar deficits in nitric oxide production were seen when stimulated by A23187, an endothelial nitric oxide synthase agonist that induces increases in nitric oxide. Cells from nonsmokers treated with menthol or clove flavorings also demonstrated impaired nitric oxide production, which suggests that these flavors cause damage similar to that found in active smokers.

In addition, Dr. Fetterman and fellow researchers exposed commercially available human aortic endothelial cells to e-cigarette flavorings, and found that burnt flavor, vanillin, cinnamon, and clove all impaired production of nitric oxide and increased production of interleukin-6 (IL-6) at all concentrations. These results suggest that the endothelium is especially sensitive to these flavors.

At the highest levels tested, all nine flavors posed danger to cells in the laboratory, and all impaired the production of nitric oxide in endothelial cells in culture. Menthol, clove, vanillin, cinnamon, and burnt flavors brought about higher levels of IL-6 and lower levels of nitric oxide, which inhibits inflammation and clotting and regulates blood vessels’ ability to widen in response to greater blood flow.

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In particular, menthol increased levels of IL-6 at high concentrations and reduced nitric oxide even at low doses. Lower levels of cinnamon, clove, strawberry, banana, and spicy cooling flavor caused cell death, as did very low levels of strawberry, suggesting that endothelial cells may be especially sensitive to this flavor. Finally, vanillin and eugenol increased cellular oxidative stress.

Researchers also heated three flavors—vanillin, eugenol, and menthol—to reproduce what happens when e-cigarettes are smoked. Vanillin and eugenol inhibited nitric oxide production, but menthol did not.

One of the strengths of this study is that researchers directly tested the effects of only the flavorings at levels likely to be reached in the body. Limitations include that they did not heat all the flavorings or include the other chemicals in e-cigarettes.

“Increased inflammation and a loss of nitric oxide are some of the first changes to occur leading up to cardiovascular disease and events like heart attacks and stroke, so they are considered early predictors of heart disease,” said Dr. Fetterman. “Our findings suggest that these flavoring additives may have serious health consequences.”

This study was funded by the National Heart, Lung, and Blood Institute, Food and Drug Administration Center for Tobacco Products, and the American Heart Association.

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• Flavorings in Tobacco Products Induce Endothelial Cell Dysfunctions