Author + information
- University of Massachusetts Medical School, Department of Medicine, Division of Cardiovascular Medicine, Worcester, Massachusetts
- ↵∗Address for correspondence:
Dr. Jane E. Freedman, University of Massachusetts Medical School, 368 Plantation Street, AS7-1051, Worcester, Massachusetts 01605-4319.
Electronic nicotine delivery systems (e-cigarettes) and vaping have been presented as alternatives to traditional combustible cigarettes for the delivery of nicotine. To deliver nicotine, glycerol or propylene glycol-based solutions known as e-liquids are typically utilized and often flavored with a variety of solutions. Although e-cigarettes are known to contain many of the harmful components of tobacco smoke, the lower content has led some to claim increased safety with usage. However, little is known about the potential toxicology of the components of e-cigarettes that are distinct from combustible cigarettes, such as flavorings. Recently, data has emerged suggesting that e-cigarette use induces an increased inflammatory response in lung epithelium, similar to tobacco smoke (1).
The question as to the safety of e-cigarettes is not trivial. Globally, in 2015 the estimated prevalence among adults was 15.2% for daily tobacco smoking, with attributable disability-adjusted life-years of 170.9 million, surpassing alcohol and illicit drugs (2). Additionally, substance-attributable mortality rates were highest for tobacco smoking (110.7 deaths per 100,000 people) (2). Although touted as beneficial in smoking cessation, there is growing alarm at the rate of use amongst teens and adults and increasing concerns that e-cigarette products are, in fact, a gateway to future tobacco abuse. Compounding the risk is the fact that, while standard cigarettes do not have flavoring, e-cigarette products often do and the hazards of these additives remains unclear.
Several recent research studies have begun to highlight the safety and health concerns of e-cigarettes. The vapor condensate from e-cigarettes appears to be significantly more toxic to in vitro cells, with enhanced production of inflammatory cytokines and chemokines as well as inhibition of potential immune function (3). The endothelium is vital in acute and chronic cardiovascular disease, and the use of combustible cigarettes has now been linked to endothelial-dependent vascular disease as shown by enhanced dysfunction including nitric oxide (NO)–dependent changes, oxidative stress, inflammation, increased thrombosis, and cell death (4). In a recent study using freshly isolated endothelial cells, participants who use nonmenthol- or menthol-flavored tobacco cigarettes had attenuated NO production compared with endothelial cells from nonsmokers. Treatment of cultured endothelial cells with flavorings also led to impaired NO release (4). Despite these observations, clear functional assessment of e-cigarette–induced endothelial dysfunction is lacking. This includes the potentially adverse contributions of e-cigarette components including the broad types of flavoring.
In this issue of the Journal, Lee et al. (5) add important data to assist in our understanding of the potential adverse mechanistic implications of e-cigarette use broadly, and specifically the potentially dangerous components. The study utilized human induced pluripotent stem cell–derived endothelial cells (iPSC-ECs) to screen endothelial function after exposure to a wide variety of e-liquids with varying nicotine concentrations, and confirmed these findings with serum collected from e-cigarette users. The use of the iPSC-ECs is notable as these cells are derived from reprograming adult somatic cells into pluripotency and have an unlimited proliferation capacity, allowing for the extensive dosing and toxicology performed, and are also useful for defining the personalized patterns of response.
Importantly, while the use of higher nicotine concentrations modestly altered endothelial toxicity, they report that the cytotoxicity between the e-liquids tested varied greatly. For example, a cinnamon-flavored liquid greatly enhanced reactive oxygen species formation and impaired endothelial function. They also noted alterations in angiogenesis, a decrease in the number of platelets, and an increase in inflammatory cytokine expression in serum of e-cigarette users. The platelet number decrease is intriguing as it suggests potential clearance of platelets that, in an inflammatory state as also described, could be prothrombotic (6). The effect of the flavorings was confirmed by transcriptomic profile of iPSC-ECs after incubation with various liquids. Using principal component analysis and broad gene expression analyses, the use of specific flavorings demonstrates a transcriptomic shift for a wide variety of relevant pathways that are nicotine-independent. Importantly, some of these findings validate gene expression changes seen in other studies using other models (7).
Although the data are strong and analyses powerful, these studies utilize culture system, a clear limitation (4,5). Due to organ specific molecular heterogeneity of the vascular endothelium, it would be critical to examine effects of the various liquids in animal models. Most importantly, these in vivo models with hard endpoints after longer-term use, or after multiple uses, would allow us to determine a causal role of these liquids in cardiovascular disease. However, despite the limitations of the culture system, the use of e-cigarettes is increasing and the data demonstrating potential harm, such as in the study by Lee et al. (5), is also growing. The use of e-cigarettes in youths and young adults was the target of the first federal agency report on these products, which stresses that they are now the most commonly used tobacco product among youth, surpassing conventional cigarettes in 2014, and are associated with the use of other tobacco products among this group. The report stresses the harmful potential of ultrafine particle inhalation, the link of flavoring chemicals with lung disease, and the presence of heavy metals including lead. Dangerously, and harking back to past conventional cigarette advertising, e-cigarettes are marketed by promoting flavors and media sources targeting children and young adults.
What can be done? Oversight and regulation are clearly needed, particularly as the risk of these products is defined. As highlighted by the findings in Lee et al. (5), additional product and safety testing appear necessary to clarify the dangerous components of these products. As with combustible cigarettes, there will be those who dispute these in vitro and nonclinical endpoint studies. However, growing data now supports that the additives in e-cigarettes may comprise a significant part of the health risk. The results by Lee et al. (5) clearly demonstrate that e-liquid flavorings had stronger effects on cytotoxicity, vascular dysfunction, and angiogenesis than nicotine. Thus, in addition to harm from the nicotine, the additives are a potential source of adverse vascular health and one that is being disproportionately placed on the young. These observations suggest that, even without the smoke of combustible cigarette products, there may be a smoldering fire of adverse health effects.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
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