E-vaporating benefits of e-vaping

This editorial refers to ‘Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2)’^†, by M. Kuntic et al., on page 2472.

Tobacco smoking is a major preventable risk factor for pulmonary, cardiovascular, and cancer morbidity and mortality. Smoking causes half a million premature deaths in the USA yearly.¹ Several public health efforts, including smoke-free policies, educational programmes, and health warnings, have been implemented to reduce tobacco use.² Traditional nicotine replacements including patches and gum are only partly effective.^3,4 A recent randomized study has shown that electronic cigarettes (e-cigarettes) are superior to these established nicotine substitutes in achieving cessation of smoking.⁵ This has led many tobacco smokers to use e-cigarettes in lieu of traditional cigarettes. The use of e-cigarettes has, however, dramatically increased beyond simply current tobacco smokers, in part due to advertising, social media campaigns, and popularity among young people. Marketing efforts have involved celebrities and have not even mentioned smoking cessation.⁶ Because of this, e-cigarette use has increased dramatically in the past 18 months,⁷ reaching ∼35% among US high school students and young adults. Alarmingly, many of these young people did not previously use tobacco.⁸ Daily e-cigarette use has recently been associated with myocardial infarction⁹ and the development of various forms of pneumonitis.¹⁰ Therefore, assessing the safety of e-cigarettes is highly relevant to public health.¹¹

In the current issue of the European Heart Journal, Kuntic et al. report a detailed study on in vivo effects of short-term e-cigarette use in humans, and extended these results to mice exposed to e-cigarette vapour.¹² These investigators demonstrated that e-cigarette use in humans is associated with a marked impairment in endothelium-dependent flow-mediated vasodilatation and an increase is pulse wave velocity, indicative of large artery stiffening. To gain mechanistic insight, the authors exposed mice to e-cigarette vapour for 3 days and showed that this altered endothelium-dependent vasodilatation, increased aortic superoxide production, and dramatically raised blood pressure. Interestingly these effects were most pronounced in the absence of nicotine. The findings of Kuntic et al. are in keeping with an earlier study by Olfert et al., who also showed that an 8-month exposure to e-cigarette vapour impaired endothelium-dependent vasodilatation and increased aortic stiffness.¹³

A major finding of Kuntic et al. is that e-cigarette vapour exposure increased vascular superoxide production (Figure 1). Superoxide reacts in a diffusion-limited fashion with nitric oxide (NO), and thus probably contributed to the reduction of endothelium-dependent vasodilatation observed in these animals and probably also in the human subjects. A major source of superoxide in vascular cells is the NADPH oxidase. The catalytic subunits of these enzymes are the Nox proteins. In keeping with this, aortic superoxide production was markedly reduced in mice lacking Nox2, as measured by HPLC analysis of dihydroethidium oxidation. While originally identified as phagocytic cell NADPH oxidase, NOX-2 is expressed in vascular endothelial cells together with other isoforms NOX-1 and NOX-4, and is up-regulated in response to a variety of vascular diseases.¹⁴ Likewise, the authors showed that Nox2^–/– mice did not develop hypertension or impaired endothelial function in response to e-cigarette vapour. In additional studies, Kuntic et al. also showed that e-cigarette exposure increased superoxide production in the brain cortex, and that this was absent in Nox2^–/– mice and prevented by the Nox2 inhibitor GSK2795039.

Figure 1.

Pleiotropic mechanisms involved in the regulation of vascular dysfunction induced by e-cigarette vaping and their potential pharmacological targeting. Created with BioRender as part of Academic License.

E-cigarette fluids contain several potentially toxic compounds including carbonyls, volatile organics, particles, trace metal elements, bacterial endotoxins, and fungal glucans.¹⁰ Using mass spectroscopy, Kuntic showed that the e-cigarette vapour used in their study contained formaldehyde, acetaldehyde, butyraldehyde, and acrolein. They further demonstrated that acrolein accumulates in the lungs of mice after e-cigarette exposure and that acrolein, when incubated with vascular segments, induces superoxide production. They also showed that aldehydes could induce components of the NADPH oxidase and cyclooxygenase-2 in macrophages.

Interestingly, Kuntic et al. observed that the untoward effects of non-nicotine-containing vapour were worse than that observed with vapour containing nicotine. For example, nicotine partially diminished norepinephrine-induced aortic contraction, aortic inducible nitric oxide synthase (iNOS) expression, and lung Nox2 expression compared with vapour without nicotine. These findings indicate that nicotine-free vapour is as deleterious or perhaps more toxic than vapour with nicotine. The in vivo effects of nicotine are complex, as it is critical for both sympathetic and parasympathetic neurotransmission and can have both anti- and pro-inflammatory effects on immune cells.

An initial intent of e-cigarette development was to provide a way to help individuals quit smoking. While this was desirable, studies like that of Kuntic et al. show that e-cigarettes are deleterious, even if they do not contain nicotine, and we do not currently know if their long-term use is beneficial compared with tobacco smoking. Moreover, it appears that the increasing popularity of e-cigarettes has not reduced the number of nicotine-addicted people and in fact the flavouring of liquids has led to their use by people who never previously smoked.¹⁵ At the time of writing, several states in the USA have now banned adding flavoured e-cigarette liquids to prevent use by young people. Kuntic et al. defined several potential therapeutic options to reduce the harm of e-cigarette vapour, including inhibition of Nox2, blockade of endothelin, and FOXO3 activation. While these provide mechanistic insight, we would strongly emphasize that the most effective way to prevent the untoward effects of e-cigarettes is to never start their use and for users to stop them as soon as possible.

 

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Funding

This paper was supported by the European Research Council Consolidator Grant (InflammaTENSION; ERC-CoG-726318; to T.J.G.). M.S. is supported by the National Science Centre, Poland (grant no. 2016/22/E/NZ4/00610). D.G.H is supported by the National Institutes of Health Grants R35HL140016 and Program Project Grant P01HL129941.

Conflict of interest: none declared.