On 2017 May 02, Lukasz Antoniewicz commented:

Thank you for your opinion.

On 2017 May 02, Zvi Herzig commented:

None of the sources with COIs relate to original data. The relevance of snus to this discussion is that it is the cleanest form of nicotine for which a wealth of long-term epidemiological evidence is available. As the American Heart Association notes Bhatnagar A, 2014:

Because most of the toxicity from cigarette smoking derives from combustion products, the health effects of smokeless tobacco could be examined to assess potential long-term adverse effects of nicotine without exposure to combustion products. Smokeless tobacco users take in as much nicotine as cigarette smokers, although not by the pulmonary route. The most extensive and rigorous epidemiological studies on smokeless tobacco use come from Scandinavia, where a large percentage of men use snus, a smokeless tobacco product that contains nicotine but relatively low levels of carcinogens and other toxins.

Rodu and Phillips do not present original data and their arguments cannot be refuted simply by citing their COIs. Similarly, Lee's meta-analyses do not present original data and are peer-reviewed. If any other meta-analysis refutes Lee's work, I'd be happy to cite it.

On 2017 May 02, Lukasz Antoniewicz commented:

As our study does not focus on snus I will not continue this debate. I do not question the scientific creditability of your citations, but I find it very interesting that among your citations some researchers clearly stated following:

Rodu B, 2015 Dr Rodu is supported by unrestricted grants from tobacco manufacturers to the University of Louisville, and by the Kentucky Research Challenge Trust Fund. Dr Phillips is partially supported by an unrestricted grant from British American Tobacco.

Lee PN, 2013 The author is a long-term consultant to the tobacco industry

Lee PN, 2009 PNL, founder of PN Lee Statistics and Computing Ltd., is an independent consultant in statistics and an advisor in the fields of epidemiology and toxicology to a number of tobacco, pharmaceutical and chemical companies.

On 2017 May 01, Zvi Herzig commented:

Snus users are exposed to equal or more more nicotine than smokers Holm H, 1992. If snus does not cause MI or stroke, this indicates that nicotine doesn't. This inference is also made by Benowitz and Burbank, as cited by Bates above.

The conclusions of the Arefalk study have been refuted by Rodu B, 2015 (see also Rodu's follow-up link).

The other possible effects of snus are unrelated to EPC mobilization. In any case, the link to type 2 diabetes is inconsistent, e.g. Rasouli B, 2017. Rodu shows that the correlation is consistent at >6 cans per week link, but "more research is needed to confirm a link" in his opinion, because of other known factors. With regards to cancers see Lee PN, 2009 Lee PN, 2013.

On 2017 Apr 28, Lukasz Antoniewicz commented:

I agree that we may speculate that nicotine mobilizes EPCs. But I do not agree on the last statement: I find it very interesting that Zvi Herzig cites studies on the tobacco product called snus and equates it to pure nicotine. As a tobacco product, Swedish snus is not comparable to pure nicotine. Swedish snus increases the risk for type 2 diabetes Carlsson S, 2017 and pancreatic cancer Luo J, 2007 and seems even to increase the risk for other types of cancer Zendehdel K, 2008, Song Z, 2010, Hirsch JM, 2012, Nordenvall C, 2013. As cited by Zvi Herzig, case fatality was increased among patients with myocardial infarction and stroke. This was confirmed by Arefalk, wo observed a 50% mortality reduction upon snus-cessation following myocardial infarction Arefalk G, 2014. In conclusion: Swedish snus is not the same thing as pure nicotine or a NRT. Swedish snus is probably not as safe as suggested by the comment of Zvi Herzig.

On 2017 Apr 25, Zvi Herzig commented:

Farsalinos and Polosa explicitly write:

Obviously, we are not implying that the elevation in EPCs that follows acute exposure to nicotine-containing e-cigarette reported by Antoniewicz et al. is beneficial to cardiovascular health.

Rather, they show that EPC mobilization doesn't indicate cardiovascular harm, as it occurs with activities known to be safe. Moreover, they note:

acute effects on EPC number could be related to a documented direct effect of nicotine.

See also Heeschen C, 2006:

Administration of nicotine increased markers of EPC mobilization.

Thus, the findings of the Antoniewicz el al appear to be a function of nicotine. Decades of epidemiological evidence don't indicate that nicotine causes myocardial infarction Hansson J, 2012 or stroke Hansson J, 2014, even though there might be some detrimental effects, as noted above.

On 2017 Apr 24, Lukasz Antoniewicz commented:

A lot of reviews explain the function of endothelial progenitor cells (EPCs). I will repeat some key points from our letter (https://www.ncbi.nlm.nih.gov/pubmed/28159320): EPCs are cells that participate in vascular repair. The trigger that releases EPCs from a pool into the blood stream is hypoxia in the vascular wall. This fact is well described in plenty reviews and studies. We know that smoking a single cigarette causes a sudden mobilization of EPCs, but this effect is temporary and EPCs return to baseline values during 24 hours (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938677/). If the vasculature is exposed to chronic stress (like in the case of daily cigarette smoking) this causes frequent releases of EPCs into the blood stream resulting in a diminished pool of EPCs. So, when analyzing EPCs in chronic smokers (but not directly after smoking a cigarette) the amount of EPCs is lower compared to non-smokers. Upon smoking cessation, this pool seems to be replenished and the amount of EPCs increases. The cited studies investigating the effects of red-wine consumption or Mediterranean diet investigate the pool of EPCs in a ”steady state” so the terms long-term and short-term are relative. We investigated the sudden effects (during hours) on EPC-release following smoking and e-cigarette inhalation.

Physical activity causes physiological stress on muscles and vessels resulting in physiological hypoxia causing a sudden mobilization of EPCs following only hours of physical activity. It is important to highlight that this mobilization is triggered as a physiological response following exercise. It is hard to argue that smoking a couple of cigarettes a day with several EPC releases has a beneficial effect on health.

Our study shows that e-cigarette inhalation has the potential to mobilize EPCs that are needed for vascular repair. We will see if daily mobilization diminishes the pool of EPCs. It remains to be shown if daily e-cigarette inhalation causes chronic changes to the vascular wall. Maybe in 20 or 30 years we will get a clear answer if the number of e-cigarette users continues to increase and epidemiological studies on myocardial infarction and stroke will give us more information. Until then, there will be a lively debate.

On 2016 Dec 23, Clive Bates commented:

In their published reply to this article, Endothelial progenitor cell release is usually considered a beneficial effect: Problems in interpreting the acute effects of e-cigarette use, Farsalinos and Polosa point out that the measured increase in endothelial progenitor cells (EPCs) is usually associated with beneficial effects, and not necessarily a cause for the concerns expressed by the authors.

Farsalinos and Polosa point out that several problem conditions are associated with lower EPC levels:

However, the increase in EPC levels is largely interpreted in the scientific literature as a beneficial effect while a reduction is interpreted as an adverse prognostic marker. Several risk factors for cardiovascular disease, such as ageing, hyperlipidemia, hypertension, obesity and diabetes, are associated with reduced levels and functional impairment of EPCs. Similar associations were found with “non-classic” risk factors such as high C-reactive protein and homocysteine, and low vitamin D levels. Smokers have lower levels of EPCs compared to nonsmokers.

They also point out that many positive conditions are associated with higher EPCs:

Various short-term or acute interventions are associated with elevated EPCs. Consumption of red wine, switching to Mediterranean diet and acute exercise are associated with elevated number of circulating EPCs in healthy subjects. EPCs increase shortly after smoking cessation (especially in light smokers), with nicotine patch users having slightly higher (but not statistically significant) elevation in EPCs after smoking cessation compared to non-users. Short-term administration of green tea also caused an increase in EPCs in young healthy smokers. In all the above-mentioned interventions, the increase in EPCs was interpreted as a beneficial effect and there was no suggestion that it was a response to vascular injury caused by the intervention

This is merely the latest of several recent analyses in which observations of acute effects of nicotine have been uncritically assumed to be a marker for a chronic cardiovascular disease risk (see Vlachopoulos C, 2016 and Carnevale R, 2016 for example), generating alarming news headlines as a result (see: E-cigs: The incendiary truth... Just 10 puffs increases your risk of heart disease, Daily Mail, 3 Dec 2016).

Please see Benowitz NL, 2016 for a more credible and complete account of the cardiovascular effects of nicotine as they relate to e-cigarettes. Benowitz and Burbank review the relevant evidence and summarise the current state of knowledge as follows:

The cardiovascular safety of nicotine is an important question in the current debate on the benefits vs. risks of electronic cigarettes and related public health policy. Nicotine exerts pharmacologic effects that could contribute to acute cardiovascular events and accelerated atherogenesis experienced by cigarette smokers. Studies of nicotine medications and smokeless tobacco indicate that the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease. Electronic cigarettes deliver nicotine without combustion of tobacco and appear to pose low-cardiovascular risk, at least with short-term use, in healthy users.

The absence of serious disease risk when nicotine is consumed through NRT or smokeless tobacco (i.e. without the products of combustion of tobacco leaf) should be a basis for reassuring and encouraging smokers considering switching to vaping.

I hope the authors and journal will take care that any misunderstandings generated by their work and the media attention that followed will be corrected and placed in context. The problem is that alarming but baseless statements about vaping risks can easily have the unintended effect of encouraging continued smoking and cause harm as a result.

On 2016 Dec 23, Clive Bates commented:

In their published reply to this article, Endothelial progenitor cell release is usually considered a beneficial effect: Problems in interpreting the acute effects of e-cigarette use, Farsalinos and Polosa point out that the measured increase in endothelial progenitor cells (EPCs) is usually associated with beneficial effects, and not necessarily a cause for the concerns expressed by the authors.

Farsalinos and Polosa point out that several problem conditions are associated with lower EPC levels:

However, the increase in EPC levels is largely interpreted in the scientific literature as a beneficial effect while a reduction is interpreted as an adverse prognostic marker. Several risk factors for cardiovascular disease, such as ageing, hyperlipidemia, hypertension, obesity and diabetes, are associated with reduced levels and functional impairment of EPCs. Similar associations were found with “non-classic” risk factors such as high C-reactive protein and homocysteine, and low vitamin D levels. Smokers have lower levels of EPCs compared to nonsmokers.

They also point out that many positive conditions are associated with higher EPCs:

Various short-term or acute interventions are associated with elevated EPCs. Consumption of red wine, switching to Mediterranean diet and acute exercise are associated with elevated number of circulating EPCs in healthy subjects. EPCs increase shortly after smoking cessation (especially in light smokers), with nicotine patch users having slightly higher (but not statistically significant) elevation in EPCs after smoking cessation compared to non-users. Short-term administration of green tea also caused an increase in EPCs in young healthy smokers. In all the above-mentioned interventions, the increase in EPCs was interpreted as a beneficial effect and there was no suggestion that it was a response to vascular injury caused by the intervention

This is merely the latest of several recent analyses in which observations of acute effects of nicotine have been uncritically assumed to be a marker for a chronic cardiovascular disease risk (see Vlachopoulos C, 2016 and Carnevale R, 2016 for example), generating alarming news headlines as a result (see: E-cigs: The incendiary truth... Just 10 puffs increases your risk of heart disease, Daily Mail, 3 Dec 2016).

Please see Benowitz NL, 2016 for a more credible and complete account of the cardiovascular effects of nicotine as they relate to e-cigarettes. Benowitz and Burbank review the relevant evidence and summarise the current state of knowledge as follows:

The cardiovascular safety of nicotine is an important question in the current debate on the benefits vs. risks of electronic cigarettes and related public health policy. Nicotine exerts pharmacologic effects that could contribute to acute cardiovascular events and accelerated atherogenesis experienced by cigarette smokers. Studies of nicotine medications and smokeless tobacco indicate that the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease. Electronic cigarettes deliver nicotine without combustion of tobacco and appear to pose low-cardiovascular risk, at least with short-term use, in healthy users.

The absence of serious disease risk when nicotine is consumed through NRT or smokeless tobacco (i.e. without the products of combustion of tobacco leaf) should be a basis for reassuring and encouraging smokers considering switching to vaping.

I hope the authors and journal will take care that any misunderstandings generated by their work and the media attention that followed will be corrected and placed in context. The problem is that alarming but baseless statements about vaping risks can easily have the unintended effect of encouraging continued smoking and cause harm as a result.