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      Acute Effects of Electronic Cigarette Inhalation on the Vasculature and the Conducting Airways

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          Abstract

          The use of electronic cigarettes has increased exponentially since its introduction onto the global market in 2006. However, short- and long-term health effects remain largely unknown due to the novelty of this product. The present study examines the acute effects of e-cigarette aerosol inhalation, with and without nicotine, on vascular and pulmonary function in healthy volunteers. Seventeen healthy subjects inhaled electronic cigarette aerosol with and without nicotine on two separate occasions in a double-blinded crossover fashion. Blood pressure, heart rate, and arterial stiffness measured by pulse wave velocity and pulse wave analysis were assessed at baseline, and then at 0 h, 2 h, and 4 h following exposure. Dynamic spirometry and impulse oscillometry were measured following vascular assessments at these time points, as well as at 6 h following exposure. e-Cigarette aerosol with nicotine caused a significant increase in heart rate and arterial stiffness. Furthermore, e-cigarette aerosol-containing nicotine caused a sudden increase in flow resistance as measured by impulse oscillometry, indicating obstruction of the conducting airways. Both aerosols caused an increase in blood pressure. The present study indicates that inhaled e-cigarette aerosol with nicotine has an acute impact on vascular and pulmonary function. Thus, chronic usage may lead to long-term adverse health effects. Further investigation is warranted.

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          The online version of this article (10.1007/s12012-019-09516-x) contains supplementary material, which is available to authorized users.

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          Most cited references 25

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          E-Cigarettes

          Electronic cigarettes (e-cigarettes) are products that deliver a nicotine-containing aerosol (commonly called vapor) to users by heating a solution typically made up of propylene glycol or glycerol (glycerin), nicotine, and flavoring agents (Figure 1) invented in their current form by Chinese pharmacist Hon Lik in the early 2000s. 1 The US patent application describes the e-cigarette device as “an electronic atomization cigarette that functions as substitutes [sic] for quitting smoking and cigarette substitutes” (patent No. 8,490,628 B2). By 2013, the major multinational tobacco companies had entered the e-cigarette market. E-cigarettes are marketed via television, the Internet, and print advertisements (that often feature celebrities) 2 as healthier alternatives to tobacco smoking, as useful for quitting smoking and reducing cigarette consumption, and as a way to circumvent smoke-free laws by enabling users to “smoke anywhere.” 3 Figure 1. Examples of different electronic cigarette (e-cigarette) products. Reproduced from Grana et al. 1 There has been rapid market penetration of e-cigarettes despite many unanswered questions about their safety, efficacy for harm reduction and cessation, and total impact on public health. E-cigarette products are changing quickly, and many of the findings from studies of older products may not be relevant to the assessment of newer products that could be safer and more effective as nicotine delivery devices. In addition, marketing and other environmental influences may vary from country to country, so patterns of use and the ultimate impact on public health may differ. The individual risks and benefits and the total impact of these products occur in the context of the widespread and continuing availability of conventional cigarettes and other tobacco products, with high levels of dual use of e-cigarettes and conventional cigarettes at the same time among adults 4–8 and youth. 9–11 It is important to assess e-cigarette toxicant exposure and individual risk, as well as the health effects, of e-cigarettes as they are actually used to ensure safety and to develop an evidence-based regulatory scheme that protects the entire population—children and adults, smokers and nonsmokers—in the context of how the tobacco industry is marketing and promoting these products. Health claims and claims of efficacy for quitting smoking are unsupported by the scientific evidence to date. To minimize the potential negative impacts on prevention and cessation and the undermining of existing tobacco control measures, e-cigarette use should be prohibited where tobacco cigarette use is prohibited, and the products should be subject to the same marketing restrictions as tobacco cigarettes. Methods Initial searches conducted via PubMed using the key words electronic cigarette, e-cigarette, and electronic nicotine delivery systems yielded 151 studies (Figure 2). Seventy-one articles presented original data and were included. Eighty articles were excluded because they were not relevant, were not in English, or were reviews or commentaries that did not provide original data, although some are cited for background and context. Searches using the same search terms were conducted using World Health Organization regional databases; only BIBLIOTECA Virtual em Salude Latin America and Caribbean included relevant papers, all of which had already been located with PubMed. Working with the World Health Organization, we also contacted investigators to locate other studies, some of which had not yet been published (submitted or in press). We also reviewed technical reports prepared by health organizations, 12–15 news articles, and relevant Web sites. The results of these searches were used to prepare a report commissioned by the World Health Organization Tobacco Free Initiative, which provides details of individual studies, including some studies that are not discussed in this article because of length constraints. 1 After the manuscript was submitted for peer review, 5 more articles became available, resulting in a total of 82 articles forming the basis for this review. Figure 2. Studies screened and selected for inclusion. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The Product E-cigarette devices are manufactured mainly in China. As of late 2013, there was wide variability in e-cigarette product engineering, including varying nicotine concentrations in the solution used to generate the nicotine aerosol (also called e-liquid), varying volumes of solution in the product, different carrier compounds (most commonly propylene glycol with or without glycerol [glycerin]), a wide range of additives and flavors, and battery voltage. Quality control is variable, 16 and users can modify many of the products, including using them to deliver other drugs such as marijuana. 17,18 These engineering differences result in variability in how e-cigarettes heat and convert the nicotine solution to an aerosol and consequently the levels of nicotine and other chemicals delivered to users and the air pollution generated by the exhaled aerosol. 19 E-liquids are flavored, including tobacco, menthol, coffee, fruit, candy, and alcohol flavors, as well as unusual flavors such as cola and Belgian waffle. 3 Flavored (conventional) tobacco products are used disproportionately by youth and initiators, 20 and cigarettes with characterizing flavors (except menthol) have been banned in the United States. Marketing and Media Research Consumer perceptions of the risks and benefits and decisions to use e-cigarettes are heavily influenced by how they are marketed. Celebrities have been used to market e-cigarettes since at least 2009. 21 Grana and Ling 3 reviewed 59 single-brand e-cigarette retail Web sites in 2012 and found that the most popular claims were that the products are healthier (95%), cheaper (93%), and cleaner (95%) than cigarettes; can be smoked anywhere (88%); can be used to circumvent smoke-free policies (71%); do not produce secondhand smoke (76%); and are modern (73%). Health claims made through text and pictorial and video representations of doctors were present on 22% of sites. Cessation-related claims (direct and indirect statements) were found on 64% of sites. Marketing on the sites commonly stated that e-cigarettes produce only “harmless water vapor.” Similar messaging strategies were being used in the United Kingdom. 22 These marketing messages have been repeated in the media. A thematic analysis of newspaper and online media coverage about e-cigarettes in the United Kingdom and Scotland from July 2007 to June 2012 found 5 themes: healthier choice, circumventing smoke-free restrictions, celebrity use, price, and risk and uncertainty. 23 Coverage often included anecdotes about having tried nicotine replacement therapies (NRTs), failing to quit, and then trying the e-cigarette (such as the celebrity endorsement by actress Katherine Heigl on the US David Letterman television program 21 ), implying that e-cigarettes are a more effective form of NRT. E-cigarette companies also have a strong presence in social media, which reinforces their marketing messages, including repeating the use of celebrity endorsements (eg, Heigl) and spreading images of the UK musical group Girls Aloud “puffing on e-cigarettes to cope with the stress of their 10th anniversary tour.” 22 Cigarette and other tobacco companies have been unable to market their products on television and radio since the 1970s. E-cigarette advertising on television and radio is mass marketing of an addictive nicotine product for use in a recreational manner to new generations who have never experienced such marketing. In an online convenience sample of 519 adult smokers and recent quitters who viewed a television commercial for Blu e-cigarettes, 76% of current smokers reported that the ad made them think about smoking cigarettes, 74% reported it made them think about quitting, and 66% said it made them likely to try an e-cigarette in the future. 24 The 34% of participants who had used e-cigarettes were significantly more likely to think about smoking cigarettes after viewing the ad than nonusers (83% and 72%, respectively), suggesting that viewing an e-cigarette commercial may induce thoughts about smoking and cue the urge to smoke. 24 Prevalence Awareness of e-cigarettes and e-cigarette trial have at least doubled among both adults and adolescents in several countries from 2008 to 2012. In the United States, awareness is more prevalent among men, but trying e-cigarettes is more prevalent among women. Almost the same percent of European Union and US adult respondents to national surveys reported having tried e-cigarettes (7% in 2012 versus 6.2% in 2011, respectively). 5,25 All population-based studies of adult use show the highest rate of e-cigarette use among current smokers, followed by former smokers, with little use among nonsmokers, although e-cigarette trial and use rose in all of these categories. 4–6 Etter and Bullen 26 followed up a sample of e-cigarette users recruited from Web sites dedicated to e-cigarettes and smoking cessation, most (72%) of whom were former smokers at baseline. At the 1-year follow up, 6% of former smokers who were daily e-cigarette users at baseline relapsed to smoking cigarettes, and almost all (92%) of the former smokers using e-cigarettes daily at baseline were still using e-cigarettes daily at follow-up. Among 36 dual users at baseline, 16 (44%) had stopped smoking after 1 year. The epidemiological, population-based studies indicate that, across countries, e-cigarettes are most commonly being used concurrently with conventional tobacco cigarettes (dual use). Consistent with marketing messages, the most common reasons given for trying e-cigarettes are for use in places where smoking is restricted, to cut down on smoking, and for help with quitting smoking. 6,27–30 Choi and Forster 31 followed up a cohort of Midwestern young adults (mean age, 24.1 years) who had never used e-cigarettes from 2010 to 2011 and found that 21.6% of baseline current smokers, 11.9% of baseline former smokers, and 2.9% of baseline nonsmokers reported having ever used e-cigarettes at follow-up. Those who believed at baseline that e-cigarettes could help with quitting smoking and perceived e-cigarettes to be less harmful than cigarettes were more likely to report experimenting with e-cigarettes at follow-up (adjusted odds ratio [OR], 1.98; 95% confidence interval [CI], 1.29–3.04; and adjusted OR, 2.34; 95% CI, 1.49–3.69, respectively). Data on e-cigarette use among adolescents are more limited but, like for adults, show rapid increases in awareness and use in 5 countries (United States, Poland, Latvia, Finland, and Korea), with higher rates of trial and current use in European countries than the United States or Korea. 9,10,32,33 In Korea, youth ever use of e-cigarettes rose from 0.5% in 2008 to 9.4% in 2011, 10 and in the United States, it rose from 3.3% in 2011 to 6.8% in 2012. 9 As with adult population-based studies, data suggest that e-cigarette use is most appealing and prevalent among youth who are also experimenting with or are current users of tobacco cigarettes. Dual use with conventional cigarettes is the predominant pattern of e-cigarette use: 61% in US middle school students and 80% among US high school students in 2011. 9 These results indicate rapid market penetration of e-cigarettes among youth, with trial among US high school students (10.0%) in 2012 even higher than the 2011 rate for adults (6.2%). 5 Despite a law prohibiting e-cigarette sales to minors, e-cigarette use among Utah youth (grades 8, 10, and 12) tripled between 2011 and 2013, with youth 3 times more likely to report current e-cigarette use than adults. 34 Although dual use with cigarettes is high, some youth experimenting with e-cigarettes have never tried a tobacco cigarette, which indicates that some youth are initiating use of nicotine, an addictive drug, with e-cigarettes. In 2012, 20.3% of middle school and 7.2% of high school ever e-cigarette users reported never smoking conventional cigarettes. 9 Similarly, in 2011 in Korea, 15% of students in grades 7 through 12 who had ever used e-cigarettes had never smoked a cigarette. 10 The Utah Department of Health found that 32% of ever e-cigarette users reported that they had never smoked conventional cigarettes. 34 E-Cigarette E-Fluid and Vapor Chemical Constituents The nicotine content of the cartridge e-liquid from some brands revealed poor concordance of labeled and actual nicotine content. 35–39 Simulated e-cigarette use revealed that individual puffs contained from 0 to 35 μg nicotine per puff. 37 Assuming a high nicotine delivery of 30 μg per puff, it would take ≈30 puffs to deliver the 1 mg nicotine typically delivered by smoking a conventional cigarette. A puff of the e-cigarette with the highest nicotine content contained 20% of the nicotine contained in a puff of a conventional cigarette. 37 Actual nicotine delivery from an e-cigarette would likely be affected by users’ smoking behavior. An analysis of UK brand e-cigarettes and the resulting aerosol demonstrated that, across brands, nicotine content of the e-liquid in the cartridges was not significantly correlated with the amount found in the resulting aerosol, indicating differences in the engineering characteristics of the device that strongly influence nicotine delivery even with a consistent puffing protocol. 40 Goniewicz et al 41 analyzed the aerosol from 12 brands of e-cigarettes, a conventional cigarette, and a nicotine inhaler for toxic and carcinogenic compounds. The levels of toxicants in the aerosol were 1 to 2 orders of magnitude lower than in cigarette smoke but higher than with a nicotine inhaler (Table 1). Table 1. Levels of Toxicants in E-Cigarette Aerosol Compared With Nicotine Inhaler and Cigarette Smoke Kim and Shin 42 analyzed the tobacco-specific nitrosamines NNN, NNK, and NAT and total tobacco-specific nitrosamines in 105 refill fluids from 11 companies in the Korean market and found nearly a 3-order-of-magnitude variation in tobacco-specific nitrosamine concentrations, with total tobacco-specific nitrosamine concentration ranging from 330 to 8600 μg/mL. Cytotoxicity Bahl et al 43 screened 41 e-cigarette refill fluids from 4 companies for cytotoxicity using 3 cell types: human pulmonary fibroblasts, human embryonic stem cells, and mouse neural stem cells. Cytotoxicity varied among products from highly toxic to low or no cytotoxicity. The authors determined that nicotine did not cause cytotoxicity, that some products were noncytotoxic to pulmonary fibroblasts but cytotoxic to both types of stem cells, and that cytotoxicity was related to the concentration and number of flavorings used. The finding that the stem cells are more sensitive than the differentiated adult pulmonary fibroblasts cells suggests that adult lungs are probably not the most sensitive system to assess the effects of exposure to e-cigarette aerosol. These findings also raise concerns about pregnant women who use e-cigarettes or are exposed to secondhand e-cigarette aerosol. In a study funded by the FlavorArt e-cigarette liquid manufacturers, Romagna et al 44 compared the cytotoxicity of aerosol produced from 21 nicotine-containing, flavored (12 tobacco flavored and 9 fruit or candied flavored) brands of e-cigarette liquid with smoke from a conventional cigarette using embryonic mouse fibroblast cells. Only aerosol from coffee-flavored e-liquid produced a cytotoxic effect (average, 51% viability at 100% concentration of solution). Farsalinos et al 45 tested cytotoxicity in cultured rat cardiac myoblasts of exposure to aerosol generated from 20 refill solutions from 5 manufacturers containing 6 to 24 mg/mL nicotine in various flavors, a “base”-only solution (50% propylene glycol and 50% glycerol), and conventional cigarette smoke. The aerosol from 3 fluids was cytotoxic at 100% and 50% dilution; 2 were tobacco flavored and 1 was cinnamon cookie flavored. Cigarette smoke was cytotoxic at 100% and all dilutions except 6.25%. Secondhand Exposure E-cigarettes do not burn or smolder the way conventional cigarettes do, so they do not emit side-stream smoke; however, bystanders are exposed to aerosol exhaled by the user. Schripp et al 46 conducted chamber studies in which subjects used 3 e-liquids (0 mg nicotine, apple flavor; 18 mg nicotine, apple flavor; 18 mg nicotine, tobacco flavor) and 1 tobacco cigarette and measured levels of several toxins and nicotine in the resulting aerosol. Three e-cigarette devices were used for these experiments: 2 that used a tank system that is directly filled with e-liquid and one that used a cartridge with a cotton fiber on which to drip the liquid. They found low levels of formaldehyde, acetaldehyde, isoprene, acetic acid, 2-butanodione, acetone, propanol, propylene glycol, and diacetin (from flavoring), traces of apple oil (3-methylbutyl-3-methylbutanoate), and nicotine (with differing levels depending on the specific protocols) emitted into the air. Toxins in the e-cigarette aerosol were at much lower levels compared with the conventional cigarette emissions. 46 In another chamber study, Flouris et al 47 compared emissions of conventional cigarettes and e-cigarettes in conditions designed to approximate a smoky bar (target air CO of 23 ppm) using machine-smoked e-cigarettes and cigarettes. E-cigarette aerosol (using a single brand of e-cigarette made in Greece and a single e-liquid with at least 60% propylene glycol, 11 mg/mL nicotine) was generated with a pump that operated for the same duration as the cigarette smoking, and aerosol was released into the room. (A person inhaling a nicotine aerosol usually absorbs 80% of the nicotine, 48 whereas the pump discharges all nicotine into the environment, so the nicotine exposure may be higher in this study than would be the case with actual secondhand aerosol exposure.) Serum cotinine in nonsmokers sitting in the chamber was similar for cigarette smoke and e-cigarette aerosol exposure (average, 0.8 ng/mL for tobacco cigarette and 0.5 ng/mL for e-cigarette). Schober et al 39 measured indoor pollution from 3 people using e-cigarettes over a 2-hour period in a realistic environment modeled on a café. They found elevated nicotine, 1,2-propanediol, glycerin, aluminum, and 7 polycyclic aromatic hydrocarbons classified as probable carcinogens by the International Agency for Research on Cancer in the room air. Czogala et al 49 conducted a chamber study of secondhand exposure to e-cigarette aerosol compared with cigarette smoke, finding that, on average, bystanders would be exposed to nicotine but at levels 1/10th that of cigarette smoke (e-cigarette aerosol, 3.32±2.49 μg/m3; cigarette smoke, 31.60±6.91 μg/m3; P=0.008). Both e-cigarette aerosol and cigarette smoke contained fine particles (PM2.5), with e-cigarette aerosol particle concentrations ranging from 6.6 to 85.0 μg/m3. E-cigarette aerosol was not a source of exposure to carbon monoxide, a key combustion element of conventional cigarette smoke. Particulate Matter E-cigarettes deliver nicotine by creating an aerosol of ultrafine particles. Fine particles can be variable and chemically complex, and the specific components responsible for toxicity and the relative importance of particle size and particle composition are generally not known. 50 Given these uncertainties, it is not clear whether the ultrafine particles delivered by e-cigarettes have health effects and toxicity similar to the ambient fine particles generated by conventional cigarette smoke or secondhand smoke. There is strong evidence, however, that frequent low or short-term levels of exposure to fine and ultrafine particles from tobacco smoke or air pollution can contribute to pulmonary and systemic inflammatory processes and increase the risk of cardiovascular and respiratory disease and death. 51–54 Fuoco et al 55 examined particle number concentration and distribution and performed a volatility analysis of the e-cigarette aerosol generated from 3 devices (2 rechargeable and 1 disposable) using 4 refill e-liquids with varying levels of nicotine and flavorants. They found that higher e-liquid nicotine content was associated with higher particle numbers in the resulting aerosol, with little effect on the particle size distribution. Longer puffing time resulted in more particles. Flavor was not associated with differences in particle number or size distribution. Consistent with other studies, 46,56–58 the particle size distribution (range of modes, ≈120–165 nm) was similar to that of conventional cigarettes, with some e-cigarettes delivering more particles than conventional cigarettes (Figure 3). Figure 3. Particle number distribution from (A) mainstream aerosol in e-liquid 1 and from (B) conventional cigarette. Reproduced from Fuoco et al 55 with permission from the publisher. Copyright © 2013 Elsevier Ltd. Zhang et al 57 examined the size of e-cigarette aerosol particles and likely deposition in the human body (using a single brand, BloogMaxXFusion) with both propylene glycol and vegetable glycerin-based liquids. Using particle size and lung ventilation rates (1 for a “reference worker” and 1 for a “heavy worker”: 1.2 and 1.688 m3/h, respectively), their human deposition model estimated that 73% to 80% of particles would be distributed into the exhaled aerosol, whereas 9% to 18% of particles would be deposited in alveoli resulting in arterial delivery, and 9% to 17% would be deposited in the head and airways, resulting in venous delivery. As expected, the heavy worker model showed more alveolar delivery across puffs compared with the reference worker, who would have more head and airway delivery. In total, ≈20% to 27% of particles are estimated to be deposited in the circulatory system and into organs from e-cigarette aerosol, which is comparable to the 25% to 35% for conventional cigarette smoke. In their study of passive exposure to exhaled e-cigarette aerosol in a simulated café, Schober et al 39 found that concentrations of fine particles in the air increased from a median of 400 particles per 1 cm3 with people simply sitting in the room for 2 hours to medians of 49 000 to 88 000 particles per 1 cm3 (depending on the e-cigarette fluid used) after 2 hours of e-cigarette use in the same room Both the e-liquid and the Poly-fil fibers that are used to absorb the e-liquid for heating and conversion to an aerosol come into contact with heating elements that contain heavy metals (tin, nickel, copper, lead, chromium). Williams et al 58 found heavy metals in samples of e-cigarette liquids and aerosol. Tin, which appeared to originate from solder joints, was found as both particles and tin whiskers in the fluid and Poly-fil, and e-cigarette fluid containing tin was cytotoxic to human pulmonary fibroblasts. E-cigarette aerosol also contained other metals, including nickel, 2 to 100 times higher than found in Marlboro cigarette smoke. The nickel and chromium nanoparticles ( 60% propylene glycol, 11 mg/mL nicotine) and a conventional cigarette according to a specified protocol, and passive exposure to e-cigarette aerosol and conventional cigarette smoke with 15 never smokers. Active cigarette smoking resulted in a significant decrease in expired lung volume (forced expiratory volume in the first second of expiration/forced inspiratory vital capacity) that was not seen with active e-cigarette use or with passive tobacco cigarette or e-cigarette exposure. Additional analysis of the data collected in this study 76 found that white cell count increased after cigarette smoking, reflecting inflammatory process–associated risk for acute cardiovascular events. Active e-cigarette use and passive exposure to e-cigarette vapor did not result in a significant increase in these biomarkers over 1 hour of exposure. Schober et al 39 found elevated levels of exhaled nitric oxide in people using a nicotine e-cigarette (but not a nicotine-free e-cigarette), which the authors attributed to pulmonary inflammation. National Vaper’s Club, a pro–e-cigarette advocacy group, published a “risk assessment” of e-cigarette and cigarette use that concluded that “neither vapor from e-liquids or cigarette smoke analytes posed a condition of ‘significant risk’ of harm to human health via the inhalation route of exposure.” 77 The authors failed to detect benzo(a)pyrene in conventional cigarette smoke despite the fact that it is an established carcinogen in cigarette smoke, and their assessment of conventional cigarettes concluded that they did not pose significant risk, both of which point to fatal errors in the data, data analysis, or both. Another report 15 funded by the Consumer Advocates for Smoke-free Alternatives Association and published on the Internet used occupational threshold limit values to evaluate the potential risk posed by several toxins in e-cigarettes, concluding that “there is no evidence that vaping produces inhalable exposures to contaminants of the aerosol that would warrant health concerns by the standards that are used to ensure safety of workplaces.” Threshold limit values are an approach to assessing health effects for occupational chemical exposures that are generally much higher (often orders of magnitude higher) than levels considered acceptable for ambient or population-level exposures. Occupational exposures also do not consider exposure to sensitive subgroups such as people with medical conditions, children, and infants who might be exposed to secondhand e-cigarette emissions, most notably nicotine. In summary, only a few studies have directly investigated the health effects of exposure to e-cigarette aerosol, but some demonstrate the ability of e-cigarette aerosol exposure to result in biological effects. Long-term biological effects are unknown at this time because e-cigarettes have not been in widespread use long enough for assessment. Effects on Cessation of Conventional Cigarettes E-cigarettes are promoted as smoking cessation aids, and many individuals who use e-cigarettes believe that they will help them quit smoking conventional cigarettes. 7,29,30 The assumption that e-cigarettes will be as effective as or more effective than pharmaceutical NRTs has also motivated support for e-cigarettes among some public health researchers and policy makers 78 and (as discussed later) formed the basis for some public policies on the regulation of e-cigarettes. Population-Based Studies There are 4 longitudinal studies 4,79–81 and 1 cross-sectional study 82 of the association between e-cigarette use and quitting conventional cigarettes (Table 2). Table 2. Population Studies of the Association Between E-Cigarette Use and Cessation of Conventional Cigarette Smoking Adkison et al 4 studied current and former smokers in the International Tobacco Control study in the United States, Canada, the United Kingdom, and Australia at baseline and 1 year later and found that e-cigarette users had a statistically significant greater reduction in cigarettes per day (e-cigarette users, 20.1 to 16.3 cigarettes per day; nonusers, 16.9 to 15.0 cigarettes per day). Although 85% of e-cigarette users reported they were using the product to quit smoking at the initial wave, e-cigarette users were no more likely to have quit 1 year later than nonusers (OR, 0.81; 95% CI, 0.43–1.53; P=0.52). Vickerman et al 80 found that ≈31% of quit-line callers surveyed 7 months after enrollment reported that they had ever tried e-cigarettes. The majority used them for 100 municipalities (including New York, Los Angeles, San Francisco, and Chicago) prohibited the use of e-cigarettes in 100% smoke-free indoor environments. 114 An additional 9 states restricted e-cigarettes in other venues such as school district property, Department of Corrections/prisons, public educational facilities and grounds, and commuter transit systems. 114 Some local and statewide smoke-free laws enacted before the introduction of e-cigarettes include language that could be interpreted as including e-cigarettes. European Union Tobacco Product Directive In February 2014, the European Parliament approved a revised European Union Tobacco Product Directive that regulates e-cigarettes with nicotine concentrations up to 20 mg/mL (an amount equal to that in a pack of cigarettes) as tobacco products. 115 E-cigarettes with higher nicotine concentrations or intended therapeutic uses will be regulated as medical devices. 116 The directive stipulates that e-cigarettes must be childproof and that packaging must include information about ingredients, adverse effects, and health warnings. 115 Refillable cartridges are allowed as long as their volume does not exceed 2 mL (but could be banned by the European Commission if at least 3 member states prohibit them on the basis of risks to human health). 115 Marketing and advertising restrictions will mirror those of tobacco products. 115 The United Kingdom In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency announced a plan to regulate e-cigarettes as medicines on the basis of the assumption that e-cigarettes function like NRTs for smokers wishing to cut down or quit. 78 As of January 2014, Medicines and Healthcare Products Regulatory Agency policies did not include any restrictions on e-cigarette marketing. 117 The antismoking advocacy group Action on Smoking and Health UK has announced that it “does not consider it appropriate to include e-cigarettes under smokefree regulations,” 118 supporting one of the e-cigarette companies’ key marketing messages that e-cigarettes can be used everywhere without the restrictions and social stigma of smoking. 3,119 Policy Recommendations E-cigarettes deliver lower levels of some of the toxins found in cigarette smoke. Main concerns about the potential of e-cigarettes to make a contribution to reducing the harm caused by cigarette smoking arise from effects on youth, dual use with cigarettes resulting in delayed or deferred quitting (among both adults and youth), and renormalization of smoking behavior. The ultimate effect of e-cigarettes on public health will depend on what happens in the policy environment. These policies should be implemented to protect public health: Prohibit the use of e-cigarettes anywhere that use of conventional cigarettes is prohibited. Prohibit the sale of e-cigarettes to anyone who cannot legally buy cigarettes or in any venues where sale of conventional cigarettes is prohibited. Subject e-cigarette marketing to the same level of restrictions that apply to conventional cigarettes (including no television or radio advertising). Prohibit cobranding e-cigarettes with cigarettes or marketing in a way that promotes dual use. Prohibit the use of characterizing flavors in e-cigarettes, particularly candy and alcohol flavors. Prohibit claims that e-cigarettes are effective smoking cessation aids until e-cigarette manufacturers and companies provide sufficient evidence that e-cigarettes can be used effectively for smoking cessation. Prohibit any health claims for e-cigarette products until and unless approved by regulatory agencies to scientific and regulatory standards. Establish standards for regulating product ingredients and functioning. In addition to being important in their own right, should these policies be put in place together with polices designed to make combustible tobacco products (eg, cigarettes, cigars, cigarillos) less desirable and available, it is possible that current conventional cigarette smokers who will not quit nicotine would shift to e-cigarettes without major dual use or youth initiation to nicotine addiction with e-cigarettes. Absent this change in the policy environment, it is reasonable to assume that the behavior patterns that have been observed for e-cigarettes will persist, which makes it unlikely that they will contribute to reducing the harm of tobacco use and could increase harm by perpetuating the life of conventional cigarettes. Conclusions Although most of the discussion of e-cigarettes among health authorities has concentrated on the product itself, its potential toxicity, and use of e-cigarettes to help people quit smoking, the e-cigarette companies have been rapidly expanding using aggressive marketing messages similar to those used to promote cigarettes in the 1950s and 1960s. E-cigarette advertising is on television and radio in many countries that have long banned similar advertising for cigarettes and other tobacco products and may be indirectly promoting smoking conventional cigarettes. Although it is reasonable to assume that, if existing smokers switched completely from conventional cigarettes (with no other changes in use patterns) to e-cigarettes, there would be a lower disease burden caused by nicotine addiction, the evidence available at this time, although limited, points to high levels of dual use of e-cigarettes with conventional cigarettes, no proven cessation benefits, and rapidly increasing youth initiation with e-cigarettes. Although some cite a desire to quit smoking by using the e-cigarette, other common reasons for using the products are to circumvent smoke-free laws and to cut down on conventional cigarettes, which may reinforce dual use patterns and delay or deter quitting. The trajectory of the dual use pattern among adults or children is unclear, but studies of youth find that as many as one third of youth who use e-cigarettes have never smoked a conventional cigarette. Nicotine is a highly addictive substance with negative effects on animal and human brain development, which is still ongoing in adolescence. 120–123 Furthermore, high rates of dual use may result in greater total public health burden and possibly increased individual risk if a smoker maintains an even low-level tobacco cigarette addiction for many years instead of quitting. Although data are limited, it is clear that e-cigarette emissions are not merely “harmless water vapor,” as is frequently claimed, and can be a source of indoor air pollution. Smoke-free policies protect nonsmokers from exposure to toxins and encourage smoking cessation. 124 One hundred percent smoke-free policies have larger effects on consumption and smoking prevalence, 125 as well as hospital admissions for myocardial infarction, stroke, and other cardiovascular and pulmonary emergencies, 126 than weaker policies. Introducing e-cigarettes into clean air environments may result in population harm if use of the product reinforces the act of smoking as socially acceptable or if use undermines the benefits of smoke-free policies. Acknowledgments We thank the following individuals for their advice and feedback: Cort Anastasio, PhD; John Balmes, MD; Cynthia Hallett, MPH; Sara Kalkhoran, MD; Lauren Lempert, JD, MPH; C. Arden Pope III, PhD; Martina Pötschke-Langer, MD, MA; Prudence Talbot, PhD; Michael Thun, MD; Gemma Vestal, JD, MPH, MBA; and the reviewers solicited by the World Health Organization Tobacco Free Initiative of the longer report prepared for it. Sources of Funding This article is a greatly condensed version of a report prepared for (and supported by) the World Health Organization Tobacco Free Initiative. Additional support came from the University of California Tobacco Related Disease Research Program 21FT-0040 and grant 1P50CA180890 from the National Cancer Institute and Food and Drug Administration Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the US FDA, or the World Health Organization. Dr Glantz is an American Legacy Foundation Distinguished Professor in Tobacco Control. Disclosures Dr Benowitz is a consultant to several pharmaceutical companies that market smoking cessation medications and has been a paid expert witness in litigation against tobacco companies. Drs Grana and Glantz report no conflicts.
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            The forced oscillation technique in clinical practice: methodology, recommendations and future developments

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              Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation.

              The endothelium holds a pivotal role in cardiovascular health and disease. Assessment of its function was until recently limited to experimental designs due to its location. The advent of novel techniques has facilitated testing on a more detailed basis, with focus on distinct pathways. This review presents available in-vivo and ex-vivo methods for evaluating endothelial function with special focus on more recent ones. The diagnostic modalities covered include assessment of epicardial and microvascular coronary endothelial function, local vasodilation by venous occlusion plethysmography and flow-mediated dilatation, arterial pulse wave analysis and pulse amplitude tonometry, microvascular blood flow by laser Doppler flowmetry, biochemical markers and bioassays, measurement of endothelial-derived microparticles and progenitor cells, and glycocalyx measurements. Insights and practical information on the theoretical basis, methodological aspects, and clinical application in various disease states are discussed. The ability of these methods to detect endothelial dysfunction before overt cardiovascular disease manifests make them attractive clinical tools for prevention and rehabilitation.
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                Author and article information

                Contributors
                lukasz.antoniewicz@ki.se
                Journal
                Cardiovasc Toxicol
                Cardiovasc. Toxicol
                Cardiovascular Toxicology
                Springer US (New York )
                1530-7905
                1559-0259
                8 April 2019
                8 April 2019
                2019
                : 19
                : 5
                : 441-450
                Affiliations
                [1 ]Division of Internal Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, 182 88 Stockholm, Sweden
                [2 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Public Health and Clinical Medicine, , Umeå University, ; Umeå, Sweden
                [3 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, The OLIN Unit, , Umeå University, ; Umeå, Sweden
                [4 ]ISNI 0000 0001 1014 8699, GRID grid.6926.b, Division of Nursing, Department of Health Science, , Luleå University of Technology, ; Luleå, Sweden
                [5 ]Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden
                Author notes

                Handling Editor: Rajiv Janardhanan.

                Article
                9516
                10.1007/s12012-019-09516-x
                6746878
                30963443
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: Swedish Heart and Lung Association
                Funded by: FundRef http://dx.doi.org/10.13039/501100007687, Svenska Läkaresällskapet;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004348, Stockholms Läns Landsting;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004047, Karolinska Institutet;
                Funded by: Swedish Heart-Lung Foundation
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                © Springer Science+Business Media, LLC, part of Springer Nature 2019

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