Skip main navigation

Impact of Electronic Cigarettes on the Cardiovascular System

Originally publishedhttps://doi.org/10.1161/JAHA.117.006353Journal of the American Heart Association. 2017;6:e006353

    Tobacco smoking is a major public health threat for both smokers and nonsmokers. There is accumulating evidence demonstrating that smoking causes several human diseases, including those affecting the cardiovascular system. Indeed, tobacco smoking is responsible for up to 30% of heart disease–related deaths in the United States each year.1 This is the single most preventable risk factor related to the development of cardiovascular disease, bringing about a trend toward tobacco harm reduction that started years ago.2 As tobacco usage declined over time in the United States, industries introduced an alternative known as electronic cigarettes (e‐cigarettes) claiming they were a healthier alternative to tobacco smoking.3

    Since then, the number of e‐cigarette users has increased significantly because of the perception that they serve as a healthy substitute to tobacco consumption with minimal or no harm, a lack of usage regulations (although that has now changed), and the appealing nature of these devices, among other reasons.4 Consequently, e‐cigarettes became the most commonly used smoking products, especially among youth, with more than a 9‐fold increase in usage from 2011 to 2015.5 Based on these considerations, it is clear that there are many unanswered questions regarding the overall safety, efficacy of harm reduction, and the long‐term health impact of these devices.

    Besides their potential negative health effects on users, there is increasing evidence that e‐cigarettes emit considerable levels of toxicants, such as nicotine, volatile organic compounds, and carbonyls, in addition to releasing particulate matter (PM).6, 7 Thus, they possess a potential harm to nonusers either through secondhand or thirdhand exposure. This is especially the case in vulnerable populations, such as children, elderly, pregnant females, and those with a history of cardiovascular disease.8 Thus, it is critical to establish e‐cigarettes' short‐ and long‐term health effects on both users and nonusers. In this review, we will discuss the current state of literature regarding the potential negative cardiovascular effects of direct/active and passive e‐cigarette exposure. Furthermore, we will review the possible impact of the individual constituents of the e‐cigarette on hemodynamics and their contribution to the development of cardiovascular disease. The notion that e‐cigarettes may negatively impact the cardiovascular system should uncover new avenues of research focused on establishing and understanding the safety of e‐cigarette usage on human health.

    E‐Cigarettes

    E‐cigarettes, also known as vape pens, e‐cigars, or vaping devices, are electronic nicotine delivering systems, which generate an aerosolized mixture containing flavored liquids and nicotine that is inhaled by the user.9 The extensive diversity of e‐cigarettes arises from the various nicotine concentrations present in e‐liquids, miscellaneous volumes of e‐liquids per product, different carrier compounds, additives, flavors, and battery voltage.9 Regardless of the exact design, each e‐cigarette device has a common functioning system, which is composed of a rechargeable lithium battery, vaporization chamber, and a cartridge (Figure 1). The lithium battery functions as the powerhouse; it is connected to the vaporization chamber that contains the atomizer9 (Figure 1). In order to deliver nicotine to the lungs, the user inhales through a mouthpiece, and the airflow triggers a sensor that then switches on the atomizer.9, 10, 11 Finally, the atomizer vaporizes liquid nicotine in a small cartridge (Figure 1) and delivers it to the lungs.9

    Figure 1.

    Figure 1. Typical e‐cigarette design. E‐cigarettes are usually composed of nicotine cartridge (e‐liquid container), vaporizing chamber, a heating coil (heats e‐liquid) followed by an atomizer (e‐vapor generator), rechargeable battery and voltage controller (which will adjust the amount of nicotine delivered during vaping), microcompressor, and LED indicator—not present in all types—to activate the battery and visually mimic the conventional cigarette, respectively. LED indicates light‐emitting diode.

    With regard to their design, there are 4 generations of devices currently on the market.4 The first‐generation e‐cigarettes are the “ciga‐like” devices, which are utilized mainly by new e‐cigarette users; they are constructed of a cartomizer (cartridge and an atomizer) with a low‐voltage battery (3.7 V).4, 12, 13, 14 Second‐generation e‐cigarettes are primarily used by more‐experienced users and are bigger in size with a refillable tank (unlike first‐generation devices).4, 13, 14 Their battery voltage is adjustable, allowing users to use low or high voltage (3–6 V) during vaping.4, 13, 14 The third‐generation devices are also known as mods and have the largest size batteries, with voltages up to 8 V.13 Finally, the fourth and most recent generation includes Sub ohm tanks (devices whose atomizer coils have a resistance of less than 1 ohm) and temperature control devices, which allow for temperature modulation during vaping. With these devices, the “vaper” can inhale huge puff volumes, leading to extremely high e‐liquid consumption per puff.4

    Taken together, there is diversity in e‐cigarette designs, which has an effect on the levels of ingredients being delivered to the user and the environment (including nonusers). This variability also complicates our ability to assess the health consequences of e‐cigarettes.

    Prevalence of e‐Cigarette Usage

    Since their introduction in 2007, e‐cigarettes have experienced widespread success among smokers, nonsmokers, pregnant females, and even youth. Their sales increased by 14‐fold since 2008,15 contributing to scientists' desire/necessity to evaluate their safety, population patterns, and usage reasons.16 Usage patterns vary depending on consumers' age group.4 In adults, usage increased over the past decade to include 3.8% of US adults, of which almost 16% are current cigarette smokers, whereas 22% are former smokers.17 Importantly, almost 3.2% of individuals who never smoked before/naïve have tried e‐cigarettes, reflecting exposure to harmful chemicals for “neoteric” purposes.17, 18 In fact, adults primarily use e‐cigarettes to discontinue smoking because they perceive them to be: (1) a healthier choice, which can reduce nicotine cravings, and (2) less harmful to nonusers in their proximity.4, 19 As for seniors, it appears that e‐cigarettes are used to stop smoking or to bypass smoke‐free policies.20, 21

    Usage of e‐cigarettes among the youth is mainly linked to their curiosity and the “appealing” flavored nature of e‐liquids.19 It is alarming that this group has the highest increase in usage18; 5.3% of all users are middle school students, and 16% are high school students. This is a 9‐ and 10‐fold increase, respectively, since 2011.18 Because the brain is only fully developed by the age of mid‐twenties, youths' exposure to nicotine may disrupt their brain development, and hinder attention and learning, while elevating susceptibility for addiction to nicotine or other drugs such as cocaine.22

    Despite the known negative consequences of tobacco smoking, many pregnant females continue to use e‐cigarettes based on their safety perception as compared with tobacco.23 Ironically, given that nicotine contributes to the negative health consequences of smoking on newborns, e‐cigarette use will likely expose the fetus to nicotine, leading to adverse effects, such as reduced cognitive deficits and perhaps even sudden infant death syndrome.22, 24, 25

    It is to be noted that aggressive marketing provoked a false perception, albeit has yet to be confirmed, about the effectiveness and safety of these devices, which further emboldened their use.20 In light of the aggressive marketing and the fact that e‐cigarettes use is growing among all populations, it is paramount to establish their safety profiles, especially in vulnerable populations, and take measures to ensure their protection.

    Public Health and e‐Cigarettes

    The long‐term health effects of e‐cigarettes have not yet been documented in humans; however, the short‐term negative effects have been suggested by several studies.8, 9, 26, 27 These studies focused mainly on the cytotoxic profile of e‐cigarettes and their effects on the respiratory tract,9, 26, 27 central nervous system,9, 10 immune system28, 29 and a few others9, 30, 31 (Table 1).

    John Wiley & Sons, Ltd

    Table 1. Potential Effects of e‐Cigarettes on Biological Systems

    SystemEffects of e‐Cigarettes
    Pulmonary system Upper and lower respiratory tract irritation9, 26, 27 Bronchitis, cough, and emphysema9, 26, 27
    Immune system Inflammation induction28 Reduce immune efficiency29
    Central nervous system Behavioral changes9 Memory impairment (animal models)9, 10 Tremor and muscle spasms10
    Miscellaneous Ocular irritation9 Contact dermatitis and burns9, 31 Nausea and vomiting9, 31 Throat and mouth irritation30, 31

    As the primary system exposed to vapors from e‐cigarettes, most reported health effects have centered on the pulmonary tract. Recent clinical and animal studies showed that (active or passive) e‐vapors/e‐cigarettes may cause irritation of both the upper and lower respiratory tract, in addition to inducing bronchospasm and cough9, 32, 33, 34; the latter effects may be attributed to a chain of inflammatory reactions through oxidative stress.28

    As for effects on other systems, e‐cigarettes also reduce, in mice, the efficiency of the immune system, as reflected by the increased susceptibility to infection with influenza A and Streptococcus pneumonia.29 As for the central nervous system, e‐cigarettes may alter brain functions, which affects the mood, learning abilities, memory, and could even induce drug dependence in both humans and animals.35, 36, 37 E‐cigarettes may also directly damage neurons and cause tremor and muscle spasms.9

    Carcinogenicity, mostly manifested in the lungs, mouth, and throat,30 is another important aspect of the e‐cigarette's negative health profile; this may be linked to nitrosamines, propylene‐glycol (the major carrier in e‐liquids), and even some flavoring agents.9, 31 In fact, one study indicated that after being heated and vaporized, propylene glycol may transform into propylene oxide, which is a class 2B carcinogen. Moreover, e‐liquid exposure was found to exert a direct cytotoxic effect on human embryonic stem cells and mouse neural stem cells, highlighting a potential harm for pregnant females.15, 32 Other adverse effects include nausea, vomiting, and contact dermatitis, as well as eye, mouth, and throat irritation.9, 31 It is noteworthy that the harm related to e‐cigarette usage reaches further beyond “beings” to include fire hazards and explosions; issues the public tends to underestimate.38, 39

    In summary, there is increasing evidence that short term e‐cigarette exposure exerts deleterious effects on multiple biological systems, but the mechanism by which these effects occur is presently unknown. While the long‐term effects have not yet been studied, one can predict that e‐cigarettes will likely cause more harm if used for extended periods, a notion that also warrants investigation.

    The Impact of e‐Cigarettes on the Cardiovascular System

    Cardiovascular disease is the major cause of death among smokers1 and is responsible for as much as 30% of heart disease–related deaths in the United States each year.1 As smokers considered safer alternatives to help them quit, they started using e‐cigarettes, in part, because they have “lower” levels of harmful constituents.19 Nevertheless, this notion should be reconciled in light of the high “sensitivity” of the cardiovascular system and evidence of a nonlinear dose‐response relationship between tobacco exposure and development of cardiovascular disease. Thus, even exposure to low levels of harmful constituents could have a pronounced effect, and, consequently, the reduction of such materials in e‐cigarettes does not assure a proportional harm reduction.40 Conversely, exposure to toxicants may not necessarily translate into a negative health effect.

    It is therefore paramount to evaluate e‐cigarette's short‐ and long‐term safety on the cardiovascular system, especially given the limited studies in this area and/or their controversial findings.28 Several studies suggest that e‐cigarette use acutely and negatively (increased) impacted vital signs, such as heart rate41, 42 and blood pressure.43, 44 In this regard, Andrea et al showed that heart rate acutely increased after e‐cigarettes use by smokers,41 which was also observed in a separate study.42 Additionally, Yan et al found that e‐cigarettes elevated both diastolic blood pressure and heart rate in smokers, but to a lesser extent when compared with tobacco cigarettes.43

    It was also found that endothelial cell dysfunction and oxidative stress, which play important roles in the pathogenesis of cardiovascular disease,45 are associated with e‐cigarettes, even a single use, but the effect was less pronounced compared with cigarette smoking.46 On the other hand, relative to cigarette smoking, e‐cigarette use caused a comparable and rapid increase in the number of circulating endothelial progenitor cells, which could be attributed to acute endothelial dysfunction and/or vascular injury.47 Given that platelets are key players in the development of cardiovascular disease—especially thrombosis and atherosclerosis—a recent in vitro study evaluated the effects of e‐cigarettes on these cells.48 Consequently, e‐cigarette vapor extracts were found to enhance activation (aggregation and adhesion) of platelets from healthy human volunteers.48

    Alternatively, some studies have shown that short‐term exposure to e‐cigarettes has no cardiovascular harm.49, 50, 51 These studies found that acute exposure to e‐cigarettes had no immediate effects on the coronary circulation, myocardial function, and arterial stiffness.10, 49, 50 Another study revealed no significant changes in smokers' heart rate after acute use of e‐cigarettes.52 However, the discrepancy in findings should be examined in the context of evidence indicating that vaping topography (e‐cigarette usage patterns such as inhalation duration and the magnitude of inhaled volume) and user's experience are critical factors in determining the health effects of e‐cigarettes.39, 53 The discrepancy in the results, aside from the user's experience and vaping topography, which could be attributed to differences in sample size, study groups (former smokers' versus nonsmokers), exposure's nature (acute versus prolonged), and wide variety of e‐cigarette products, makes it difficult to draw conclusions regarding the cardiovascular health consequences of e‐cigarettes. Of note, the long‐term effects of e‐cigarettes have not been studied, nor has the mechanism(s) by which they exert their effects on the cardiovascular system.

    Although some studies support and promote the idea that e‐cigarettes could be a safer alternative to tobacco, it is important to consider (and address) the public safety of these devices to nonusers who are in proximity and would be subject to secondhand vaping/exposure.54 Furthermore, a new threat, thirdhand vaping/exposure, has been discovered; it arises from exposure to e‐cigarette residues remaining on surfaces in areas where vaping took place.55 Given that secondhand and even thirdhand exposure to tobacco smoke exerts toxicity, including the cardiovascular system,56 whether e‐cigarettes are a source of secondhand or thirdhand vapors was investigated. Subsequent studies provided substantial evidence that e‐cigarettes are not an emission‐free device; instead, they negatively affect indoor air quality. Specifically, e‐cigarette vaping was found to release various potentially noxious constituents.57, 58

    Although the indoor use of e‐cigarettes was found to result in lower levels of “secondhand and thirdhand” residues, compared with tobacco smoke,59 these hazards are still a health threat to those who are involuntarily exposed (nonusers). The latter notion should be considered with survey findings that e‐cigarette users (unfortunately) do not consider laws that prohibit tobacco smoking to apply to them and hence vape in smoke‐free areas.60 This is consistent with another survey that showed a large proportion of middle and high school students have been exposed to secondhand vapes.61 Thus, research should be initiated to evaluate health effects of secondhand and thirdhand vaping, which would, in turn, inform (stricter) e‐cigarette regulations.

    The Impact of e‐Cigarette Toxicants/Constituents on the Cardiovascular System

    There are limited studies on the health effects of e‐cigarettes, particularly on the cardiovascular system. Therefore, to gain a better understanding of their possible/potential harm, we sought to review the effects of constituents/toxicants known to exist in e‐cigarettes. In this regard, e‐liquids and e‐vapors are a source of a large number of these chemicals,7, 10, 53, 57, 62, 63, 64, 65, 66 affecting several biological systems37, 43, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 (Table 2). The levels of some of these toxicants in e‐cigarette aerosols are claimed to be lower than in tobacco smoke. For instance, several studies have shown that e‐cigarette usage results in lower volatile organic compounds levels compared with the combustible cigarette.64, 89, 90 Notably, the levels of e‐cigarette chemicals appear to vary between studies, attributed to the wide range of products on the market, different nicotine concentrations, study designs, vaping techniques (puffing topography), and users' experiences.91 Nevertheless, most studies do support the presence of carbonyl compounds, nicotine, and particulate matter in e‐cigarette liquids and/or vapors,8, 9 and those will be the focus of the discussion in the following sections.

    John Wiley & Sons, Ltd

    Table 2. Chemicals Emitted in e‐Cigarette Vapors and Their Potential Health Effects

    ChemicalDetected Concentration RangeBiological System Affected
    NicotineND to 36.6 mg/mL10, 62, 63 Lung tumor promoter67 Addiction67 Gastrointestinal carcinogen67 Raises blood pressure and heart rate68 Reduce brain development in adolescents37
    CotinineNDaReduce fertility and reproduction69
    AldehydesAcetaldehyde0.11 to 2.94 μg/15 puffs53, 64, 65 Carcinogen70 Aggravation of alcohol‐induced liver damage71
    Acrolein0.044 to 6.74 μg/15 puffs53, 64, 65 Ocular irritation72 Respiratory irritation72 Gastrointestinal irritation72
    Formaldehyde0.2 to 27.1 μg/15 puffs53, 64, 65 Carcinogen68 Bronchitis, pneumonia, and increase asthma risk in children73, 74 Ocular, nasal, and throat irritant74
    o‐Methyl benzaldehydeND to 7.1 μg/15 puffs7Unknown
    AcetoneND to 91.27 Gastric distress75 Weakness of extremities and headache75 Ocular irritation75
    Volatile organic compoundsPropylene glycol0 to 82.875 mg/15 puffs7 Throat and airways irritation.76 Carcinogen68 Gastric distress68 Increase asthma risk in children68 Ocular irritation68
    Glycerin75 to 225 μg/15 puffs57 Lipoid pneumonia77 Ocular, dermal, and pulmonary irritant78
    3‐Methylbutyl‐3‐methylbutanoate1.5 to 16.5 μg/15 puffs57Unknown
    Toluene<0.63 μg/15 puffs64 CNS damage79 Renal damage80
    NitrosaminesNNN0.8 to 4.3 ng/e‐cigarette64Carcinogen87
    NNK1.1 to 28.3 ng/e‐cigarette64Carcinogen87
    MetalsChromiumND to 0.0105 μg/15 puffs7, 66 Pulmonary irritation and inflammation, nasal mucosa atrophy and ulcerations81 Nasal mucosa atrophy, reduce fertility and reproduction82
    CadmiumND to 0.022 μg/15 puffs64, 66 Increase risk of lung cancer83 Pulmonary and nasal irritation83
    Lead0.025 to 0.57 μg/15 puffs64, 66 Hypertension induction83, 84, 88 Renal damage88 CNS damage84, 88
    Nickel0.0075 to 0.29 μg/15 puffs64, 66 Carcinogen43 CNS and pulmonary damage85 Renal and hepatic toxicity85

    ND indicates not detected; CNS, central nervous system; NNK, 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone; NNN, N‐nitrosamines.

    aVariable concentrations found in plasma after using e‐cigarettes.92

    The Impact of Nicotine on the Cardiovascular System

    Nicotine, which is the major constituent in most smoking products, is considered a strong alkaloid that can be absorbed by various routes: oral mucosa, lungs, skin, or gut.93 After absorption, nicotine is metabolized by the liver into cotinine as one of the metabolites.94 Most e‐liquids contain nicotine at concentrations that vary between 0 and 36.6 mg/mL.95 Interestingly, it has been reported that several e‐cigarette brands inaccurately labeled nicotine concentration,96 and, in fact, some of the “nicotine free” brands apparently contain some.8 As expected, e‐liquids with higher nicotine concentrations deliver more nicotine than those with lower concentrations.43, 97

    Nicotine delivery to the human body is affected by other factors, such as the type of device used.39 Thus, studies on first‐generation e‐cigarettes reported delivery of low concentrations of nicotine to the bloodstream,98 unlike newer‐generation devices (equipped with a high‐capacity battery).13 To this end, Farsalinos et al showed a 35% to 72% increase in nicotine delivery with newer generations of e‐cigarettes, relative to first‐generation devices.13 Furthermore, although studies have shown that conventional cigarettes result in quicker and 60% to 80% higher plasma nicotine levels,45, 98, 99 e‐cigarettes vaping still could result in comparable levels92 especially with experienced smokers who can adjust the topography of vaping.53, 62, 100, 101 However, e‐cigarette users take a longer time to reach such levels.53, 92 Consistent with its systemic uptake, comparable saliva and plasma levels were reported for cotinine, which is considered one of the major metabolites and a marker of nicotine, in both e‐cigarette users and conventional smokers.92, 102, 103 Collectively, these studies support the notion that e‐cigarette usage results in increased nicotine delivery to the human body.

    Studies with conventional cigarettes showed that nicotine increased the risk of cardiovascular disease in smokers, including the development of acute coronary disease,46 elevated blood pressure,104 and heart failure.105 As for nicotine effects on thrombogenesis, it seems to be controversial, with studies suggesting it to be elevated,106, 107 reduced,108 or not affected109; but this discrepancy could be attributed to the dose of nicotine used,110 route of administration,111 and the method used to measure platelet function. Additionally, it was established that nicotine induces endothelial dysfunction,112 angiogenesis,113 inflammation,114 and lipogenesis, which may increase thrombosis risk. Conversely and interestingly, nicotine delivered from nicotine replacement therapy was not found to be associated with increased cardiovascular diseases risk.104 This finding could be attributed to the standardized dose‐delivery system of nicotine replacement therapy, in which the nicotine dose is reduced over a short period of time.104 Thus, it seems that the cardiovascular effects of nicotine depend on the dose delivered and its distribution kinetics.115, 116, 117 Given that the pharmacokinetics of nicotine delivery to human body by e‐vaping seems to be different from tobacco smoking, both in the magnitude and the speed by which peak levels are reached,118 it is essential to evaluate whether “e‐vaped” nicotine has an effect on cardiovascular system.

    Unfortunately, studies on e‐cigarette nicotine effects have been limited, and controversial. A study by D'Ruiz et al indicated an elevation in heart rate after using (different brands of) e‐cigarettes, which correlated with elevation in plasma nicotine levels. This is consistent with findings that both heart rate and plasma nicotine were elevated after 5 minutes of the first puff, and throughout 1 hour of the ad‐lib period in e‐cigarette users.43 A separate study found no changes in heart rate in e‐cigarette users, and no increase in nicotine plasma levels were observed.52 However, these “guilt by association” studies do not provide a direct cause‐and‐effect relationship between nicotine concentration and human hemodynamics. This notion seems to be consistent with a recent in vitro study by Rubenstein et al, which indicated that the enhanced activity of human platelets upon exposure to e‐vapor extracts was independent of nicotine.48 It is clear that further investigation is warranted to address and better understand the short‐ and long‐term effects of nicotine delivered by e‐cigarettes on the cardiovascular system.

    Additional concerns related to e‐cigarettes include nicotine dependence and toxicity, given that the nicotine concentrations found in plasma of e‐cigarette smokers are high enough to produce and maintain nicotine dependence, especially in youth. This may explain why many adolescents shift to tobacco smoking in their adulthood or cannot abandon vaping easily.22 E‐cigarettes may also present higher risks of nicotine toxicity, especially for children, because some incidents of ingesting e‐liquids were reported.9, 119 In fact, the number of calls to poison centers for ingestion of e‐liquids increased from “one per month in September 2010 to 215 per month in February 2014”.120 Thus, the Child Nicotine Poisoning Prevention Act was initiated in January 2016; this required e‐cigarettes manufacturers to use child‐resistant e‐liquid packaging.

    Concerns also exist for passive exposure to nicotine (nonusers); there is considerable evidence that e‐vapors are a source of nicotine contamination.103 Indeed, examination of indoor air quality revealed a significant elevation of air nicotine concentrations, which was commensurate with an increase in nicotine levels in plasma and saliva of nonusers.90 In agreement with these results, salivary concentrations of cotinine were found to be elevated in nonusers living with e‐cigarette users.103, 121 In addition to this, a detectable amount of nicotine was found on the surfaces of e‐cigarette users' homes, suggesting a potential risk for thirdhand exposure.55, 59 Taken together, these data advocate that e‐cigarettes are a source of secondhand and thirdhand exposure to nicotine, especially in sensitive or vulnerable populations, regardless of whether its levels from passive exposure to e‐vapors are similar or lower than those from tobacco smoke.

    The Impact of Carbonyl Compounds on the Cardiovascular System

    In addition to nicotine, e‐cigarettes emit other potentially harmful constituents like carbonyls; this includes aldehydes, such as formaldehyde, acetaldehyde, and acrolein,64, 122 which result from thermal degradation of propylene glycol and glycerol (most commonly used solvents in e‐liquids123). As was the case with nicotine, newer generations of e‐cigarettes reportedly result in comparable carbonyls levels relative to cigarettes (voltage dependent).122, 124 In this regard, whereas some studies showed that levels of aldehydes increased significantly under high voltage, or “dry‐puff” conditions,122, 125 recent studies confirmed their presence even under normal puffing conditions.126 Interestingly, levels of the acrolein metabolite, 3‐HPMA, were found to be elevated in urine samples obtained from e‐cigarette smokers when compared with nonsmokers, confirming its systemic delivery to the human body.127 On the other hand, levels of 3‐HPMA were reduced by 83% when tobacco smokers switched to e‐cigarettes and were similar to levels observed in those who quit smoking.128 The presence of the aforementioned aldehydes represents a major health concern; in fact, formaldehyde was classified as a carcinogen and acetaldehyde as a potential carcinogen by the International Agency for Research on Cancer.129

    Aside from their cytotoxic effects, animal studies suggest that aldehydes exert various negative cardiovascular effects.130, 131, 132 Given the limited clinical studies evaluating the effects of e‐cigarette aldehydes on the human cardiovascular system, we will rely on and extrapolate evidence from non‐e‐cigarette sources. In this regard, animal studies revealed that formaldehyde exposure altered the heart rate,132 by a sympathetic nerve activity,132 and it also altered blood pressure133 and cardiac contractility.131 Additionally, subacute and chronic inhalation of formaldehyde was associated with cardiac oxidative stress and, consequently, cardiac cell damage.134 With regard to platelets, it was shown that total platelet count significantly increased in mice exposed to formaldehyde gas130; this effect should be considered in the context of the importance of platelets in hemostasis and their role in thrombotic disorders. As for acetaldehyde, elevated blood pressure and heart rate were reported in animals following inhalation of variable doses, which could be attributed to its sympathomimetic effect.135, 136 It is noteworthy that formaldehyde and acetaldehyde concentrations used in these studies are comparable to the levels generated by e‐cigarettes. Collectively, studies clearly suggest potential harm from exposure to aldehydes, which could serve as a basis for future and further studies focusing on the cardiovascular consequences of their chronic exposure in real‐life e‐cigarette settings.

    Exposure from smoking and other sources to acrolein, the other carbonyl, is associated with a wide range of cardiovascular toxicity.137 Thus, inhalation of only 3 ppm of acrolein caused an increase in systolic, diastolic, and mean arterial blood pressure in an animal model.138 Furthermore, acrolein‐mediated autonomic imbalance caused an increase in the risk of developing arrhythmia in rats.139 Additionally, it has been suggested that acrolein can directly induce myocardial dysfunction and cardiomyopathy.140 As for the mechanisms of acrolein‐induced cardiotoxicity, the following is some of what has been proposed thus far: the formation of myocardial protein‐acrolein adduct, induction of oxidative stress signaling, upregulation of proinflammatory cytokines, and inhibition of cardioprotective signaling.140, 141

    In line with the negative effects on the vasculature, acrolein can result in vascular injury by impairing vascular repair capacity, as well as increasing the risk of thrombosis and atherosclerosis, a possible result of endothelial dysfunction, dyslipidemia, and platelet activation, among others.142, 143, 144 Moreover, Sithu et al found that inhalation of acrolein vapor, generated from either acrolein liquid or tobacco smoke, results in a prothrombotic phenotype in mice.145 Acute (5 ppm for 6 hours) or subchronic (1 ppm for 6 hours/day for 4 days) exposure to acrolein, regardless of its source, induced platelet activation and aggregation.145 Additionally, an increase in acrolein‐protein adduct in platelets was observed, which suggests its systemic delivery and that it exerts a direct effect on platelets.145 In support of this notion, a human study revealed a correlation between levels of acrolein metabolite (ie, 3‐HPMA) and platelet‐leukocyte aggregates, in addition to increased risk of cardiovascular diseases.146 The effects of acrolein on the cardiovascular system are summarized in Figure 2.

    Figure 2.

    Figure 2. Effects of acrolein on the cardiovascular system. Wide ranges of cardiovascular effects of acrolein inhalation from smoking and ambient air pollution are reported in animal studies.138, 139, 142, 146

    Although acrolein sources were different in these studies, to gain insight regarding their relevance and applicability to e‐cigarettes, we converted the concentrations emitted from e‐cigarettes to ppm, as reported by several studies, taking into account puff volumes64, 147, 148, 149 (Table 3). Thus, based on the average of 120 puffs/day reported in the literature,101 our calculated levels of acrolein emitted by e‐cigarette users per day were found to vary between 0.00792 and 8.94 ppm/day (Table 3). Because its harmful cardiovascular levels fall within this range, acrolein emitted from e‐cigarettes may produce similar harm, which warrants investigation.

    John Wiley & Sons, Ltd

    Table 3. Acrolein Concentrations Emitted in e‐Cigarette Vapors

    ReferencePuff VolumeAcrolein Concentration/15 puffsaAcrolein Concentration/d (120 puffs)Acrolein Concentration ppmbAcrolein Concentration ppm/d (120 puffs)
    Goniewicz et al6470 mL0.07 to 4.19 μg0.564 to 33.516 μg6.6×10−5 to 0.00390.00792 to 0.468
    Uchiyama et al14755 mL3.15 to 24 μg25.2 to 192 μg0.0038 to 0.0290.456 to 3.48
    Gillman et al14855 mL0.3 to 82.5 μg2.4 to 660 μg0.00036 to 0.10.0432 to 12
    Flora et al14955 mL61.5 μg492 μg0.07458.94

    a15 puffs=1 conventional cigarette.

    bppm=μg/mL, to convert μg/puff to ppm, we divided the concentration (μg) by the volume of each puff (mL).

    ppm=concentration(μg)volume (mL)

    As mentioned before, an additional concern, that is often forgotten or ignored, is that e‐cigarettes can be a source of secondhand or thirdhand exposure to aldehydes (and other toxicants) for nonusers.150, 151 Indeed, under human puffing conditions, indoor air quality was found to be reduced, attributed to aldehydes emission in e‐cigarette vapors.57 Even though detected levels were low, they may still pose a health concern, especially in people with a history of cardiovascular disease, as well as in children, casino/housekeeping workers, and in pregnant women. Hence, the safety of exposure to low levels of aldehydes for extended periods of time needs to be examined in nonusers who live with e‐cigarette users or work in places where their use is allowed.

    The Impact of PM on the Cardiovascular System

    Another health concern related to e‐cigarette usage is the generation of fine and ultrafine particles, known as PM, which represents the solid and liquid particles suspended in the air. PM2.5, which includes particles with a diameter of 2.5 μm or less, will be the focus of this section because of their small size; this enables them to easily penetrate airways and reach circulation, thereby causing a potential hazard to the respiratory and cardiovascular systems.152 Several studies evaluated their presence in e‐cigarette vapors and concluded that significant levels of PM2.5 are indeed exhaled by e‐cigarette users.58 The number of particles and size distribution in emitted PM in e‐vapors were found to vary depending on the e‐liquid, nicotine concentration, and puffing topography12, 101, 153 and seem to be comparable to those generated from tobacco smoke.153, 154

    Several studies, conducted under controlled conditions that almost resemble real‐life settings, revealed a significant increase in PM2.5 concentrations in rooms and/or experimental chambers in which e‐cigarettes were consumed by human subjects.57, 65, 90 This highlights e‐cigarettes as a source of PM2.5 secondhand exposures.57, 65, 90 In fact, PM2.5 concentrations increased dramatically (125–330‐folds) in hotel rooms where e‐cigarette use was allowed for 2 days, compared with the same rooms before active vaping occurred.155 Surprisingly, these concentrations of PM2.5 are higher than the reported values from tobacco smoking in Hookah cafes and indoor bars.155 On the other hand, it has been shown that the level of PM2.5 in houses of e‐cigarette users was 95% lower than those from homes of conventional cigarette users.58 Collectively, these studies provide evidence that e‐cigarette users do indeed exhale PM2.5, thus putting themselves as well as nonusers under health risks.

    Epidemiological and clinical studies suggest a strong association between human exposure to PM2.5 and the risk of cardiovascular disease development. Specifically, these studies showed that exposure to PM2.5 from ambient air pollution and/or tobacco smoking is linked to hypertension,156 coronary artery disease,157 myocardial infarction,158, 159 atherosclerosis,156 arrhythmia160 as well as mortality relative risk.161, 162 Interestingly, risk of atherosclerosis was reported to increase with long‐term exposure to ambient air PM2.5, and to be higher in elderly, female, and nonsmoker participants,163 underscoring the sensitivity of special populations. This notion is consistent with reports that exposure of the elderly population with a history of cardiovascular disease to PM2.5 for only 28 days was accompanied with higher resting cerebrovascular resistance and increased mean arterial blood pressure.164

    The physiomolecular mechanisms underlying the aforementioned effects are divided into a direct and indirect pathway, as summarized in Figure 3.156 The direct pathway is mediated by the delivery of PM2.5 into the bloodstream, thereby targeting multiple organs.165, 166 Thus, if ion channels and calcium regulation are affected by PM2.5, it could lead to contractile dysfunction and arrhythmia,165, 167 whereas vascular dysfunction and thrombus formation can result from producing local oxidative stress and inflammation.168, 169, 170 Regarding the indirect pathway, PM2.5‐induced cardiovascular toxicity is associated with the development of inflammatory responses and modulation of the autonomic nervous system.167 Thus, deposition of PM2.5 on alveoli was found to trigger the release of a host of proinflammatory mediators, vasoactive molecules, and reactive oxygen species into the circulation. These will subsequently affect vascular integrity and induce thrombogenesis.168, 170 As for PM2.5 modulation of the autonomic nervous system, it results in increased vasoconstriction and change in heart rate variability, which will potentially enhance the risk of developing arrhythmias and thrombosis.171

    Figure 3.

    Figure 3. Effects of particulate matter (PM2.5) on the cardiovascular system. PM2.5 exposure from tobacco and environment/ambient negatively affects the cardiovascular system either directly or indirectly. The direct pathway is mediated by the delivery of PM2.5 into the bloodstream. The indirect pathway is attributed to deposition of PM2.5 in lungs and a modulation of autonomic nervous system. Oxidative stress is triggered by both pathways and induces local and systemic inflammatory processes. PM2.5 indicates particulate matter less than 2.5 microns in diameter.

    Importantly, it has been found that the dose‐response relationship between PM exposure and cardiovascular mortality is also nonlinear,172 and that a consequential adverse cardiovascular outcome can happen as a result of exposure to low levels.172 Interestingly, it was suggested that PM2.5 is responsible for more than 90% of the predicted harm caused by thirdhand smoke pollutants.173 Although, clearly, PM2.5 from ambient air pollution and smoking exerts harmful effects on the cardiovascular system, its mere presence—as a result of e‐cigarette use—does not mean that it will have an effect; this issue should be investigated.

    Studies have shown that e‐cigarette PM2.5, even from a single puff, undergoes cardiopulmonary delivery into the systemic circulation,174 resulting in a significant amount of deposition in the respiratory tree.175 Furthermore, in vitro experiments documented a venous absorption between 7% and 18% of the total e‐aerosol and arterial absorption through the alveoli between 8% and 19%.174 Finally, a recent in vitro study concluded that PM2.5 may be the primary constituent that mediates e‐cigarette‐induced platelet activation and aggregation.48 Based on these considerations, it is important to examine the negative health effects of short‐ and long‐term (active and passive) exposure to e‐cigarettes PM2.5.

    Recent Regulatory Updates

    Because of the growing evidence that e‐cigarettes' present potential harm to public health, and the “skyrocketing” usage among youth, the US Food and Drug Administration issued new legislation (on August 8, 2016) that extended their regulations to e‐cigarettes. This is expected to protect public health, minimize the risks associated with e‐cigarettes and reduce youth's exposure to these devices. Under this expansion, manufacturers will be required to report all ingredients and undergo a premarket review to obtain permission to market their products.176 Furthermore, selling of e‐cigarettes to those aged <18 years is now prohibited, as is selling any tobacco products in vending machines (unless in an adult‐only facility).176 Of note, the tobacco 21 movement, a regulation that advocates for raising the minimum legal sale age for tobacco products to 21, was followed during 2016 only in 2 states (California and Hawaii). However, as of March 2017, the pattern is expanding to include at least 220 localities across the United States.177 Nonetheless, and unfortunately, e‐cigarettes are still available for purchase from online vendors, which would be the first alternative for youth. Thus, this aspect/“loophole” should be covered/closed by state legislation or by stricter rules from the US Food and Drug Administration.

    The Public Health and Tobacco Policy Center report revealed that even though 31 states have (state) restrictions and laws addressing where e‐cigarettes usage is allowed, only 10 of 31 prohibited their use wherever tobacco is prohibited effective January 2017. The majority of the remaining states prohibit vaping in schools, day care facilities, and a few on campuses.178 However, concerns remain regarding the use of e‐cigarettes at work and public places across the country, which results in exposing nonusers to potentially harmful vapors.

    Conclusion

    Although much is known about smoking‐induced cardiovascular toxicity, little is known about that of e‐cigarettes. This is an issue that continues to be a subject of debate. Nevertheless, based on the current body of evidence, e‐cigarettes are not emission free (as some believe) and, in fact, they emit various potentially harmful and toxic chemicals. Whether or not the levels of these toxicants are lower than traditional smoking remains controversial. In this connection, recent studies showed that e‐cigarettes‐emitted chemicals reach levels comparable to tobacco smoke, and those levels vary depending on multiple factors, including types of devices, e‐liquid, vaping topography, and vaping experience.179 Given the sensitivity of the cardiovascular system and its “smoke” nonlinear dose‐response/toxicity relationship, it is important to evaluate the cardiovascular safety of e‐cigarettes.

    Although it was originally argued that e‐cigarettes are “harm free,” the present prevailing belief is that they are “reduced harm” alternatives to conventional cigarettes. This latter notion is still debatable and not supported by conclusive evidence, especially considering the wide variation between e‐cigarette products. Even if that were the case, their harm can still extend to innocent/bystander nonsmokers through secondhand and thirdhand vaping, including children, pregnant women, casino/housekeeping workers, and people with preexisting cardiovascular and other diseases.

    The widespread and increasing usage of e‐cigarettes in the United States is concerning because of the lack of studies on the long‐term health effects of these devices on biological systems. Therefore, future research should establish, under real‐life conditions, not only the long‐term, but also the short‐term negative effects of e‐cigarette usage, on both users (active) and nonusers (passive), and provide mechanistic insights regarding these effects. These should, in turn, guide and shape policy for further evidence‐based vaping control. Ultimately, we hope to underscore the need for prevention of exposure to various forms of vaping, especially in vulnerable populations like children and youth.

    Acknowledgments

    The authors thank Julie A. Rivera, MA, of The University of Texas at El Paso for proofreading and editing this manuscript. The authors also acknowledge the support of the staff of the Smoke Free Initiative, supported by a grant from Paso del Norte Health Foundation (to J.O.R.).

    Disclosures

    None.

    Footnotes

    *Correspondence to: Fatima Z. Alshbool, PharmD, PhD, 500 W University Dr, El Paso, TX 79968. E‐mail:

    References

    • 1 Centers for Disease Control and Prevention . CDC death report. 2014.Google Scholar
    • 2 Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest. 2007; 131:1557–1566.Google Scholar
    • 3 Berg CJ, Barr DB, Stratton E, Escoffery C, Kegler M. Attitudes toward e‐cigarettes, reasons for initiating e‐cigarette use, and changes in smoking behavior after initiation: a pilot longitudinal study of regular cigarette smokers. Open J Prev Med. 2014; 4:789–800.Google Scholar
    • 4 Brandon TH, Goniewicz ML, Hanna NH, Hatsukami DK, Herbst RS, Hobin JA, Ostroff JS, Shields PG, Toll BA, Tyne CA, Viswanath K, Warren GW. Electronic nicotine delivery systems: a policy statement from the American Association for Cancer Research and the American Society of Clinical Oncology. J Clin Oncol. 2015; 33:952–963.Google Scholar
    • 5 Corey CG, Ambrose BK, Apelberg BJ, King BA. Flavored tobacco product use among middle and high school students—United States, 2014. MMWR Morb Mortal Wkly Rep. 2015; 64:1066–1070.Google Scholar
    • 6 Farsalinos KE, Gillman IG, Melvin MS, Paolantonio AR, Gardow WJ, Humphries KE, Brown SE, Poulas K, Voudris V. Nicotine levels and presence of selected tobacco‐derived toxins in tobacco flavoured electronic cigarette refill liquids. Int J Environ Res Public Health. 2015; 12:3439–3452.Google Scholar
    • 7 Cheng T. Chemical evaluation of electronic cigarettes. Tob Control. 2014; 23(Suppl 2):ii11–ii17.Google Scholar
    • 8 Kaisar MA, Prasad S, Liles T, Cucullo L. A decade of e‐cigarettes: limited research & unresolved safety concerns. Toxicology. 2016; 365:67–75.Google Scholar
    • 9 Grana R, Benowitz N, Glantz SA. E‐cigarettes: a scientific review. Circulation. 2014; 129:1972–1986.Google Scholar
    • 10 Farsalinos KE, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Ther Adv Drug Saf. 2014; 5:67–86.Google Scholar
    • 11 Giroud C, de Cesare M, Berthet A, Varlet V, Concha‐Lozano N, Favrat B. E‐cigarettes: a review of new trends in cannabis use. Int J Environ Res Public Health. 2015; 12:9988–10008.Google Scholar
    • 12 Bhatnagar A, Whitsel LP, Ribisl KM, Bullen C, Chaloupka F, Piano MR, Robertson RM, McAuley T, Goff D, Benowitz N; American Heart Association Advocacy Coordinating Committee, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Quality of Care and Outcomes Research . Electronic cigarettes: a policy statement from the American Heart Association. Circulation. 2014; 130:1418–1436.Google Scholar
    • 13 Farsalinos KE, Spyrou A, Tsimopoulou K, Stefopoulos C, Romagna G, Voudris V. Nicotine absorption from electronic cigarette use: comparison between first and new‐generation devices. Sci Rep. 2014; 4:4133.Google Scholar
    • 14 Crotty Alexander LE, Vyas A, Schraufnagel DE, Malhotra A. Electronic cigarettes: the new face of nicotine delivery and addiction. J Thorac Dis. 2015; 7:E248–E251.Google Scholar
    • 15 E‐cigarette use among youth and young adults. A Report of the Surgeon General. 2016.Google Scholar
    • 16 Palazzolo DL. Electronic cigarettes and vaping: a new challenge in clinical medicine and public health. A literature review. Front Public Health. 2013; 1:56.Google Scholar
    • 17 Schoenborn CA, Gindi RM. Electronic cigarette use among adults: United States, 2014. NCHS Data Brief. 2015; 217:1–8.Google Scholar
    • 18 Centers for Disease Control and Prevention . Youth and tobacco use. 2015.Google Scholar
    • 19 Patel D, Davis KC, Cox S, Bradfield B, King BA, Shafer P, Caraballo R, Bunnell R. Reasons for current e‐cigarette use among U.S. adults. Prev Med. 2016; 93:14–20.Google Scholar
    • 20 Cataldo JK, Petersen AB, Hunter M, Wang J, Sheon N. E‐cigarette marketing and older smokers: road to renormalization. Am J Health Behav. 2015; 39:361–371.Google Scholar
    • 21 Pearson JL, Richardson A, Niaura RS, Vallone DM, Abrams DB. E‐cigarette awareness, use, and harm perceptions in US adults. Am J Public Health. 2012; 102:1758–1766.Google Scholar
    • 22 US Department of Health and Human Services eneral ARotS . E‐cigarette use among youth and young adults: a report of the Surgeon General. 2016.Google Scholar
    • 23 Baeza‐Loya S, Viswanath H, Carter A, Molfese DL, Velasquez KM, Baldwin PR, Thompson‐Lake DG, Sharp C, Fowler JC, De La Garza R, Salas R. Perceptions about e‐cigarette safety may lead to e‐smoking during pregnancy. Bull Menninger Clin. 2014; 78:243–252.Google Scholar
    • 24 Wickstrom R. Effects of nicotine during pregnancy: human and experimental evidence. Curr Neuropharmacol. 2007; 5:213–222.Google Scholar
    • 25 Spindel ER, McEvoy CT. The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of e‐cigarettes. Am J Respir Crit Care Med. 2016; 193:486–494.Google Scholar
    • 26 Scheffler S, Dieken H, Krischenowski O, Forster C, Branscheid D, Aufderheide M. Evaluation of e‐cigarette liquid vapor and mainstream cigarette smoke after direct exposure of primary human bronchial epithelial cells. Int J Environ Res Public Health. 2015; 12:3915–3925.Google Scholar
    • 27 Vardavas CI, Anagnostopoulos N, Kougias M, Evangelopoulou V, Connolly GN, Behrakis PK. Short‐term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide. Chest. 2012; 141:1400–1406.Google Scholar
    • 28 Lerner CA, Sundar IK, Yao H, Gerloff J, Ossip DJ, McIntosh S, Robinson R, Rahman I. Vapors produced by electronic cigarettes and e‐juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. PLoS One. 2015; 10:e0116732.Google Scholar
    • 29 Sussan TE, Gajghate S, Thimmulappa RK, Ma J, Kim JH, Sudini K, Consolini N, Cormier SA, Lomnicki S, Hasan F, Pekosz A, Biswal S. Exposure to electronic cigarettes impairs pulmonary anti‐bacterial and anti‐viral defenses in a mouse model. PLoS One. 2015; 10:e0116861.Google Scholar
    • 30 Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e‐cigarette aerosols. N Engl J Med. 2015; 372:392–394.Google Scholar
    • 31 Hess CA, Olmedo P, Navas‐Acien A, Goessler W, Cohen JE, Rule AM. E‐cigarettes as a source of toxic and potentially carcinogenic metals. Environ Res. 2017; 152:221–225.Google Scholar
    • 32 Callahan‐Lyon P. Electronic cigarettes: human health effects. Tob Control. 2014; 23:ii36–ii40.Google Scholar
    • 33 Hua M, Alfi M, Talbot P. Health‐related effects reported by electronic cigarette users in online forums. J Med Internet Res. 2013; 15:e59.Google Scholar
    • 34 Cho JH, Paik SY. Association between electronic cigarette use and asthma among high school students in South Korea. PLoS One. 2016; 11:e0151022.Google Scholar
    • 35 Ponzoni L, Moretti M, Sala M, Fasoli F, Mucchietto V, Lucini V, Cannazza G, Gallesi G, Castellana CN, Clementi F, Zoli M, Gotti C, Braida D. Different physiological and behavioural effects of e‐cigarette vapour and cigarette smoke in mice. Eur Neuropsychopharmacol. 2015; 25:1775–1786.Google Scholar
    • 36 Yamada H, Bishnoi M, Keijzers KF, van Tuijl IA, Small E, Shah HP, Bauzo RM, Kobeissy FH, Sabarinath SN, Derendorf H, Bruijnzeel AW. Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats. Pharmacol Biochem Behav. 2010; 95:401–409.Google Scholar
    • 37 Dutra LM, Glantz SA. Electronic cigarettes and conventional cigarette use among U.S. adolescents: a cross‐sectional study. JAMA Pediatr. 2014; 168:610–617.Google Scholar
    • 38 Colaianni CA, Tapias LF, Cauley R, Sheridan R, Schulz JT, Goverman J. Injuries caused by explosion of electronic cigarette devices. Eplasty. 2016; 16:ic9.Google Scholar
    • 39 Brown CJ, Cheng JM. Electronic cigarettes: product characterisation and design considerations. Tob Control. 2014; 23(suppl 2):ii4–ii10.Google Scholar
    • 40 Bhatnagar A. Cardiovascular perspective of the promises and perils of e‐cigarettes. Circ Res. 2016; 118:1872–1875.Google Scholar
    • 41 Vansickel AR, Eissenberg T. Electronic Cigarettes: Effective Nicotine Delivery After Acute Administration. Nicotine & Tobacco Research. 2013; 15(1):267–270. doi:10.1093/ntr/ntr316.Google Scholar
    • 42 Nides MA, Leischow SJ, Bhatter M, Simmons M. Nicotine blood levels and short‐term smoking reduction with an electronic nicotine delivery system. Am J Health Behav. 2014; 38:265–274.Google Scholar
    • 43 Yan XS, D'Ruiz C. Effects of using electronic cigarettes on nicotine delivery and cardiovascular function in comparison with regular cigarettes. Regul Toxicol Pharmacol. 2015; 71:24–34.Google Scholar
    • 44 Vlachopoulos C, Ioakeimidis N, Abdelrasoul M, Terentes‐Printzios D, Georgakopoulos C, Pietri P, Stefanadis C, Tousoulis D. Electronic cigarette smoking increases aortic stiffness and blood pressure in young smokers. J Am Coll Cardiol. 2016; 67:2802–2803.Google Scholar
    • 45 Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function and oxidative stress in cardiovascular diseases. Circ J. 2009; 73:411–418.Google Scholar
    • 46 Carnevale R, Sciarretta S, Violi F, Nocella C, Loffredo L, Perri L, Peruzzi M, Marullo AG, De Falco E, Chimenti I, Valenti V, Biondi‐Zoccai G, Frati G. Acute impact of tobacco vs electronic cigarette smoking on oxidative stress and vascular function. Chest. 2016; 150:606–612.Google Scholar
    • 47 Antoniewicz L, Bosson JA, Kuhl J, Abdel‐Halim SM, Kiessling A, Mobarrez F, Lundbäck M. Electronic cigarettes increase endothelial progenitor cells in the blood of healthy volunteers. Atherosclerosis. 2016; 255:179–185.Google Scholar
    • 48 Hom S, Chen L, Wang T, Ghebrehiwet B, Yin W, Rubenstein DA. Platelet activation, adhesion, inflammation, and aggregation potential are altered in the presence of electronic cigarette extracts of variable nicotine concentrations. Platelets. 2016; 27:694–702.Google Scholar
    • 49 Szoltysek‐Boldys I, Sobczak A, Zielinska‐Danch W, Barton A, Koszowski B, Kosmider L. Influence of inhaled nicotine source on arterial stiffness. Przegl Lek. 2014; 71:572–575.Google Scholar
    • 50 Farsalinos KE, Tsiapras D, Kyrzopoulos S, Savvopoulou M, Voudris V. Acute effects of using an electronic nicotine‐delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes. BMC Cardiovasc Disord. 2014; 14:78.Google Scholar
    • 51 Farsalinos K, Tsiapras D, Kyrzopoulos S, Stefopoulos C, Spyrou A, Tsakalou M, Avramidou E, Vasilopoulou D, Romagna G, Voudris V. Immediate effects of electronic cigarette use on coronary circulation and blood carboxyhemoglobin levels: comparison with cigarette smoking. Eur Heart J. 2013; 34(suppl_1):102. doi: 10.1093/eurheartj/eht307.102Google Scholar
    • 52 Vansickel AR, Cobb CO, Weaver MF, Eissenberg TE. A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects. Cancer Epidemiol Biomark Prev. 2010; 19:1945–1953.Google Scholar
    • 53 Vansickel AR, Eissenberg T. Electronic cigarettes: effective nicotine delivery after acute administration. Nicotine Tob Res. 2013; 15:267–270.Google Scholar
    • 54 US Department of Health and Human Services . 14th report on carcinogens (RoC). 2016.Google Scholar
    • 55 Goniewicz ML, Lee L. Electronic cigarettes are a source of thirdhand exposure to nicotine. Nicotine Tob Res. 2015; 17:256–258.Google Scholar
    • 56 Karim ZA, Alshbool FZ, Vemana HP, Adhami N, Dhall S, Espinosa EV, Martins‐Green M, Khasawneh FT. Third‐hand smoke: impact on hemostasis and thrombogenesis. J Cardiovasc Pharmacol. 2015; 66:177–182.Google Scholar
    • 57 Schripp T, Markewitz D, Uhde E, Salthammer T. Does e‐cigarette consumption cause passive vaping?Indoor Air. 2013; 23:25–31.Google Scholar
    • 58 Fernandez E, Ballbe M, Sureda X, Fu M, Salto E, Martinez‐Sanchez JM. Particulate matter from electronic cigarettes and conventional cigarettes: a systematic review and observational study. Curr Environ Health Rep. 2015; 2:423–429.Google Scholar
    • 59 Bush D, Goniewicz ML. A pilot study on nicotine residues in houses of electronic cigarette users, tobacco smokers, and non‐users of nicotine‐containing products. Int J Drug Policy. 2015; 26:609–611.Google Scholar
    • 60 Shi Y, Cummins SE, Zhu SH. Use of electronic cigarettes in smoke‐free environments. Tob Control. 2017; 26(e1):e19–e22.Google Scholar
    • 61 Agaku IT, Singh T, Rolle I, Olalekan AY, King BA. Prevalence and determinants of secondhand smoke exposure among middle and high school students. Pediatrics. 2016; 137:e20151985.Google Scholar
    • 62 Schroeder MJ, Hoffman AC. Electronic cigarettes and nicotine clinical pharmacology. Tob Control. 2014; 23(suppl 2):ii30–ii35.Google Scholar
    • 63 Goniewicz ML, Kuma T, Gawron M, Knysak J, Kosmider L. Nicotine levels in electronic cigarettes. Nicotine Tob Res. 2013; 15:158–166.Google Scholar
    • 64 Goniewicz ML, Knysak J, Gawron M, Kosmider L, Sobczak A, Kurek J, Prokopowicz A, Jablonska‐Czapla M, Rosik‐Dulewska C, Havel C, Jacob P, Benowitz N. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014; 23:133–139.Google Scholar
    • 65 Schober W, Szendrei K, Matzen W, Osiander‐Fuchs H, Heitmann D, Schettgen T, Jorres RA, Fromme H. Use of electronic cigarettes (e‐cigarettes) impairs indoor air quality and increases FeNO levels of e‐cigarette consumers. Int J Hyg Environ Health. 2014; 217:628–637.Google Scholar
    • 66 Williams M, Villarreal A, Bozhilov K, Lin S, Talbot P. Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol. PLoS One. 2013; 8:e57987.Google Scholar
    • 67 Mishra A, Chaturvedi P, Datta S, Sinukumar S, Joshi P, Garg A. Harmful effects of nicotine. Indian J Med Paediatr Oncol. 2015; 36:24–31.Google Scholar
    • 68 Schaller K, Ruppert L, Kahnert S, Bethke C, Nair U, Pötschke‐Langer M. Electronic cigarettes—an overview. Tobacco Prevention and Tobacco Control German Cancer Research Center, Heidelberg. 2013;19.Google Scholar
    • 69 Shaw JL, Oliver E, Lee KF, Entrican G, Jabbour HN, Critchley HO, Horne AW. Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha‐7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy. Am J Pathol. 2010; 177:2509–2515.Google Scholar
    • 70 Xing YF, Xu YH, Shi MH, Lian YX. The impact of PM2.5 on the human respiratory system. J Thorac Dis. 2016; 8:E69–E74.Google Scholar
    • 71 Lieber CS. Metabolic effects of acetaldehyde. Biochem Soc Trans. 1988; 16:241–247.Google Scholar
    • 72 Faroon O, Roney N, Taylor J, Ashizawa A, Lumpkin MH, Plewak DJ. Acrolein health effects. Toxicol Ind Health. 2008; 24:447–490.Google Scholar
    • 73 Fischer MH. The toxic effects of formaldehyde and formalin. J Exp Med. 1905; 6:487–518.Google Scholar
    • 74 McGwin G, Lienert J, Kennedy JI. Formaldehyde exposure and asthma in children: a systematic review. Environ Health Perspect. 2010; 118:313–317.Google Scholar
    • 75 National Research Council . Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2. Washington, DC: The National Academies Press; 1984.Google Scholar
    • 76 Kienhuis AS, Soeteman‐Hernandez LG, Bos PM, Cremers HW, Klerx WN, Talhout R. Potential harmful health effects of inhaling nicotine‐free shisha‐pen vapor: a chemical risk assessment of the main components propylene glycol and glycerol. Tob Induc Dis. 2015; 13:15.Google Scholar
    • 77 Breland AB, Spindle T, Weaver M, Eissenberg T. Science and electronic cigarettes: current data, future needs. J Addict Med. 2014; 8:223–233.Google Scholar
    • 78 Pisinger C, Dossing M. A systematic review of health effects of electronic cigarettes. Prev Med. 2014; 69:248–260.Google Scholar
    • 79 Filley CM, Halliday W, Kleinschmidt‐DeMasters BK. The effects of toluene on the central nervous system. J Neuropathol Exp Neurol. 2004; 63:1–12.Google Scholar
    • 80 Tang HL, Chu KH, Cheuk A, Tsang WK, Chan HW, Tong KL. Renal tubular acidosis and severe hypophosphataemia due to toluene inhalation. Hong Kong Med J. 2005; 11:50–53.Google Scholar
    • 81 Wilbur S, Abadin H, Fay M, Yu D, Tencza B, Ingerman L, Klotzbach J, James S. Toxicological Profile for Chromium. Atlanta, GA: Agency for Toxic Substances and Disease Registry (US); 2012.Google Scholar
    • 82 Elbetieha A, Al‐Hamood MH. Long‐term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility. Toxicology. 1997; 116:39–47.Google Scholar
    • 83 Faroon O, Ashizawa A, Wright S, Tucker P, Jenkins K, Ingerman L, Rudisill C. Toxicological Profile for Cadmium. Atlanta, GA: Agency for Toxic Substances and Disease Registry (US); 2012.Google Scholar
    • 84 Flora G, Gupta D, Tiwari A. Toxicity of lead: a review with recent updates. Interdiscip Toxicol. 2012; 5:47–58.Google Scholar
    • 85 Das KK, Das SN, Dhundasi SA. Nickel, its adverse health effects & oxidative stress. Indian J Med Res. 2008; 128:412–425.Google Scholar
    • 86 National Toxicology P . NTP 11th report on carcinogens. Rep Carcinog. 2004; 11:1–A32.Google Scholar
    • 87 Alavanja M, Bartsch H, Allen N, Bhisey RA. Personal habits and indoor combustions. Int Agency Res Cancer. 2012; 100E:319–328.Google Scholar
    • 88 Abadin H, Ashizawa A, Stevens YW, Llados F, Diamond G, Sage G, Citra M, Quinones A, Bosch SJ, Swarts SG. Toxicological Profile for Lead. Atlanta, GA: Agency for Toxic Substances and Disease Registry (US); 2007.Google Scholar
    • 89 Marco E, Grimalt JO. A rapid method for the chromatographic analysis of volatile organic compounds in exhaled breath of tobacco cigarette and electronic cigarette smokers. J Chromatogr A. 2015; 1410:51–59.Google Scholar
    • 90 Czogala J, Goniewicz ML, Fidelus B, Zielinska‐Danch W, Travers MJ, Sobczak A. Secondhand exposure to vapors from electronic cigarettes. Nicotine Tob Res. 2014; 16:655–662.Google Scholar
    • 91 Callahan‐Lyon P. Electronic cigarettes: human health effects. Tob Control. 2014; 23(suppl 2):ii36–ii40.Google Scholar
    • 92 Marsot A, Simon N. Nicotine and cotinine levels with electronic cigarette: a review. Int J Toxicol. 2016; 35:179–185.Google Scholar
    • 93 Langone JJ, Gjika HB, Van Vunakis H. Nicotine and its metabolites. Radioimmunoassays for nicotine and cotinine. Biochemistry. 1973; 12:5025–5030.Google Scholar
    • 94 Sobkowiak R,Lesicki A. [Absorption, metabolism and excretion of nicotine in humans]. Postepy Biochem. 2013; 59:33–44.Google Scholar
    • 95 Goniewicz ML, Gupta R, Lee YH, Reinhardt S, Kim S, Kim B, Kosmider L, Sobczak A. Nicotine levels in electronic cigarette refill solutions: a comparative analysis of products from the U.S., Korea, and Poland. Int J Drug Policy. 2015; 26:583–588.Google Scholar
    • 96 Buettner‐Schmidt K, Miller DR, Balasubramanian N. Electronic cigarette refill liquids: child‐resistant packaging, nicotine content, and sales to minors. J Pediatr Nurs. 2016; 31:373–379.Google Scholar
    • 97 Ramôa CP, Hiler MM, Spindle TR, Lopez AA, Karaoghlanian N, Lipato T, Breland AB, Shihadeh A, Eissenberg T. Electronic cigarette nicotine delivery can exceed that of combustible cigarettes: a preliminary report. Tob Control. 2016; 25:e6–e9.Google Scholar
    • 98 Bullen C, McRobbie H, Thornley S, Glover M, Lin R, Laugesen M. Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross‐over trial. Tob Control. 2010; 19:98–103.Google Scholar
    • 99 Eissenberg T. Electronic nicotine delivery devices: ineffective nicotine delivery and craving suppression after acute administration. Tob Control. 2010; 19:87–88.Google Scholar
    • 100 St Helen G, Havel C, Dempsey DA, Jacob P, Benowitz NL. Nicotine delivery, retention and pharmacokinetics from various electronic cigarettes. Addiction. 2016; 111:535–544.Google Scholar
    • 101 Robinson RJ, Hensel EC, Morabito PN, Roundtree KA. Electronic cigarette topography in the natural environment. PLoS One. 2015; 10:e0129296.Google Scholar
    • 102 Etter JF. Levels of saliva cotinine in electronic cigarette users. Addiction. 2014; 109:825–829.Google Scholar
    • 103 Flouris AD, Chorti MS, Poulianiti KP, Jamurtas AZ, Kostikas K, Tzatzarakis MN, Wallace Hayes A, Tsatsakis AM, Koutedakis Y. Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function. Inhal Toxicol. 2013; 25:91–101.Google Scholar
    • 104 Centers for Disease Control and Prevention (US); National Center for Chronic Disease Prevention and Health Promotion (US); Office on Smoking and Health (US).How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking‐Attributable Disease: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention (US); 2010.Google Scholar
    • 105 Villarreal FJ, Hong D, Omens J. Nicotine‐modified postinfarction left ventricular remodeling. Am J Physiol. 1999; 276:H1103–H1106.Google Scholar
    • 106 Hioki H, Aoki N, Kawano K, Homori M, Hasumura Y, Yasumura T, Maki A, Yoshino H, Yanagisawa A, Ishikawa K. Acute effects of cigarette smoking on platelet‐dependent thrombin generation. Eur Heart J. 2001; 22:56–61.Google Scholar
    • 107 Fahim MA, Nemmar A, Singh S, Hassan MY. Antioxidants alleviate nicotine‐induced platelet aggregation in cerebral arterioles of mice in vivo. Physiol Res. 2011; 60:695–700.Google Scholar
    • 108 Girdhar G, Xu S, Bluestein D, Jesty J. Reduced‐nicotine cigarettes increase platelet activation in smokers in vivo: a dilemma in harm reduction. Nicotine Tob Res. 2008; 10:1737–1744.Google Scholar
    • 109 Ljungberg LU, Persson K, Eriksson AC, Green H, Whiss PA. Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro. Toxicol In Vitro. 2013; 27:932–938.Google Scholar
    • 110 Pfueller SL, Burns P, Mak K, Firkin BG. Effects of nicotine on platelet function. Haemostasis. 1988; 18:163–169.Google Scholar
    • 111 Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol. 1993; 22:1159–1167.Google Scholar
    • 112 Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014; 34:509–515.Google Scholar
    • 113 Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL, Cooke JP. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001; 7:833–839.Google Scholar
    • 114 Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol. 2004; 43:1731–1737.Google Scholar
    • 115 Porchet HC, Benowitz NL, Sheiner LB, Copeland JR. Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics. J Clin Invest. 1987; 80:1466–1471.Google Scholar
    • 116 Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997; 29:1422–1431.Google Scholar
    • 117 Benowitz NL, Porchet H, Sheiner L, Jacob P. Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther. 1988; 44:23–28.Google Scholar
    • 118 Benowitz NL, Hukkanen J, Jacob P. Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 2009; 192:29–60.Google Scholar
    • 119 Payne JD, Michaels D, Orellana‐Barrios M, Nugent K. Electronic cigarette toxicity. J Prim Care Community Health. 2016; 8:100–102.Google Scholar
    • 120 CDC . New CDC study finds dramatic increase in e‐cigarette‐related calls to poison centers. 2014.Google Scholar
    • 121 Ballbè M, Martínez‐Sánchez JM, Sureda X, Fu M, Pérez‐Ortuño R, Pascual JA, Saltó E, Fernández E. Cigarettes vs. e‐cigarettes: passive exposure at home measured by means of airborne marker and biomarkers. Environ Res. 2014; 135:76–80.Google Scholar
    • 122 Hutzler C, Paschke M, Kruschinski S, Henkler F, Hahn J, Luch A. Chemical hazards present in liquids and vapors of electronic cigarettes. Arch Toxicol. 2014; 88:1295–1308.Google Scholar
    • 123 Wang P, Chen W, Liao J, Matsuo T, Ito K, Fowles J, Shusterman D, Mendell M, Kumagai K. A device‐independent evaluation of carbonyl emissions from heated electronic cigarette solvents. PLoS One. 2017; 12:e0169811.Google Scholar
    • 124 Geiss O, Bianchi I, Barrero‐Moreno J. Correlation of volatile carbonyl yields emitted by e‐cigarettes with the temperature of the heating coil and the perceived sensorial quality of the generated vapours. Int J Hyg Environ Health. 2016; 219:268–277.Google Scholar
    • 125 Kosmider L, Sobczak A, Fik M, Knysak J, Zaciera M, Kurek J, Goniewicz ML. Carbonyl compounds in electronic cigarette vapors: effects of nicotine solvent and battery output voltage. Nicotine Tob Res. 2014; 16:1319–1326.Google Scholar
    • 126 Bhatnagar A. E‐cigarettes and cardiovascular disease risk: evaluation of evidence, policy implications, and recommendations. Curr Cardiovasc Risk Rep. 2016; 10:24.Google Scholar
    • 127 Hecht SS, Carmella SG, Kotandeniya D, Pillsbury ME, Chen M, Ransom BW, Vogel RI, Thompson E, Murphy SE, Hatsukami DK. Evaluation of toxicant and carcinogen metabolites in the urine of e‐cigarette users versus cigarette smokers. Nicotine Tob Res. 2015; 17:704–709.Google Scholar
    • 128 O'Connell G, Graff DW, D'Ruiz CD. Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers. Toxicol Mech Methods. 2016; 26:443–454.Google Scholar
    • 129 Humans IWGotEoCRt . Formaldehyde, 2‐butoxyethanol and 1‐tert‐butoxypropan‐2‐ol. IARC Monogr Eval Carcinog Risks Hum. 2006; 88:1–478.Google Scholar
    • 130 Zhang Y, Liu X, McHale C, Li R, Zhang L, Wu Y, Ye X, Yang X, Ding S. Bone marrow injury induced via oxidative stress in mice by inhalation exposure to formaldehyde. PLoS One. 2013; 8:e74974.Google Scholar
    • 131 Tani T, Horiguchi Y. Effects of formaldehyde on cardiac function. Jpn J Pharmacol. 1990; 52:563–572.Google Scholar
    • 132 Tani T, Kogi K, Horiguchi Y. Inhibitory effects of formaldehyde inhalation on the cardiovascular and respiratory systems in unanesthetized rabbits. Jpn J Pharmacol. 1986; 40:551–559.Google Scholar
    • 133 Tani T, Satoh S, Horiguchi Y. The vasodilator action of formaldehyde in dogs. Toxicol Appl Pharmacol. 1978; 43:493–499.Google Scholar
    • 134 Gulec M, Songur A, Sahin S, Ozen OA, Sarsilmaz M, Akyol O. Antioxidant enzyme activities and lipid peroxidation products in heart tissue of subacute and subchronic formaldehyde‐exposed rats: a preliminary study. Toxicol Ind Health. 2006; 22:117–124.Google Scholar
    • 135 Egle JL. Effects of inhaled acetaldehyde and propionaldehyde on blood pressure and heart rate. Toxicol Appl Pharmacol. 1972; 23:131–135.Google Scholar
    • 136 James TN, Bear ES. Cardiac effects of some simple aliphatic aldehydes. J Pharmacol Exp Ther. 1968; 163:300–308.Google Scholar
    • 137 Henning RJ, Johnson GT, Coyle JP, Harbison RD. Acrolein can cause cardiovascular disease: a review. Cardiovasc Toxicol. 2017; 17:227–236.Google Scholar
    • 138 Perez CM, Hazari MS, Ledbetter AD, Haykal‐Coates N, Carll AP, Cascio WE, Winsett DW, Costa DL, Farraj AK. Acrolein inhalation alters arterial blood gases and triggers carotid body‐mediated cardiovascular responses in hypertensive rats. Inhalation Toxicol. 2015; 27:54–63.Google Scholar
    • 139 Hazari MS, Haykal‐Coates N, Winsett DW, Krantz QT, King C, Costa DL, Farraj AK. TRPA1 and sympathetic activation contribute to increased risk of triggered cardiac arrhythmias in hypertensive rats exposed to diesel exhaust. Environ Health Perspect. 2011; 119:951–957.Google Scholar
    • 140 Luo J, Hill BG, Gu Y, Cai J, Srivastava S, Bhatnagar A, Prabhu SD. Mechanisms of acrolein‐induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure. Am J Physiol Heart Circ Physiol. 2007; 293:H3673–H3684.Google Scholar
    • 141 Wang GW, Guo Y, Vondriska TM, Zhang J, Zhang S, Tsai LL, Zong NC, Bolli R, Bhatnagar A, Prabhu SD. Acrolein consumption exacerbates myocardial ischemic injury and blocks nitric oxide‐induced PKCepsilon signaling and cardioprotection. J Mol Cell Cardiol. 2008; 44:1016–1022.Google Scholar
    • 142 Wheat LA, Haberzettl P, Hellmann J, Baba SP, Bertke M, Lee J, McCracken J, O'Toole TE, Bhatnagar A, Conklin DJ. Acrolein inhalation prevents vascular endothelial growth factor‐induced mobilization of Flk‐1+/Sca‐1+ cells in mice. Arterioscler Thromb Vasc Biol. 2011; 31:1598–1606.Google Scholar
    • 143 Srivastava S, Sithu SD, Vladykovskaya E, Haberzettl P, Hoetker DJ, Siddiqui MA, Conklin DJ, D'Souza SE, Bhatnagar A. Oral exposure to acrolein exacerbates atherosclerosis in apoE‐null mice. Atherosclerosis. 2011; 215:301–308.Google Scholar
    • 144 Conklin DJ, Barski OA, Lesgards JF, Juvan P, Rezen T, Rozman D, Prough RA, Vladykovskaya E, Liu S, Srivastava S, Bhatnagar A. Acrolein consumption induces systemic dyslipidemia and lipoprotein modification. Toxicol Appl Pharmacol. 2010; 243:1–12.Google Scholar
    • 145 Sithu SD, Srivastava S, Siddiqui MA, Vladykovskaya E, Riggs DW, Conklin DJ, Haberzettl P, O'Toole TE, Bhatnagar A, D'Souza SE. Exposure to acrolein by inhalation causes platelet activation. Toxicol Appl Pharmacol. 2010; 248:100–110.Google Scholar
    • 146 DeJarnett N, Conklin DJ, Riggs DW, Myers JA, O'Toole TE, Hamzeh I, Wagner S, Chugh A, Ramos KS, Srivastava S, Higdon D, Tollerud DJ, DeFilippis A, Becher C, Wyatt B, McCracken J, Abplanalp W, Rai SN, Ciszewski T, Xie Z, Yeager R, Prabhu SD, Bhatnagar A. Acrolein exposure is associated with increased cardiovascular disease risk. J Am Heart Assoc. 2014; 3:e000934. DOI: 10.1161/JAHA.114.000934.Google Scholar
    • 147 Uchiyama S, Senoo Y, Hayashida H, Inaba Y, Nakagome H, Kunugita N. Determination of chemical compounds generated from second‐generation e‐cigarettes using a sorbent cartridge followed by a two‐step elution method. Anal Sci. 2016; 32:549–555.Google Scholar
    • 148 Gillman IG, Kistler KA, Stewart EW, Paolantonio AR. Effect of variable power levels on the yield of total aerosol mass and formation of aldehydes in e‐cigarette aerosols. Regul Toxicol Pharmacol. 2016; 75:58–65.Google Scholar
    • 149 Flora JW, Meruva N, Huang CB, Wilkinson CT, Ballentine R, Smith DC, Werley MS, McKinney WJ. Characterization of potential impurities and degradation products in electronic cigarette formulations and aerosols. Regul Toxicol Pharmacol. 2016; 74:1–11.Google Scholar
    • 150 Bahl V, Weng NJ, Schick SF, Sleiman M, Whitehead J, Ibarra A, Talbot P. Cytotoxicity of thirdhand smoke and identification of acrolein as a volatile thirdhand smoke chemical that inhibits cell proliferation. Toxicol Sci. 2016; 150:234–246.Google Scholar
    • 151 Zhang X, Pu J. E‐cigarette use among US adolescents: secondhand smoke at home matters. Int J Public Health. 2016; 61:209–213.Google Scholar
    • 152 Anderson JO, Thundiyil JG, Stolbach A. Clearing the air: a review of the effects of particulate matter air pollution on human health. J Med Toxicol. 2012; 8:166–175.Google Scholar
    • 153 Fuoco FC, Buonanno G, Stabile L, Vigo P. Influential parameters on particle concentration and size distribution in the mainstream of e‐cigarettes. Environ Pollut. 2014; 184:523–529.Google Scholar
    • 154 Ingebrethsen BJ, Cole SK, Alderman SL. Electronic cigarette aerosol particle size distribution measurements. Inhal Toxicol. 2012; 24:976–984.Google Scholar
    • 155 Soule EK, Maloney SF, Spindle TR, Rudy AK, Hiler MM, Cobb CO. Electronic cigarette use and indoor air quality in a natural setting. Tob Control. 2017; 26:109–112.Google Scholar
    • 156 Nelin TD, Joseph AM, Gorr MW, Wold LE. Direct and indirect effects of particulate matter on the cardiovascular system. Toxicol Lett. 2012; 208:293–299.Google Scholar
    • 157 Puett RC, Hart JE, Yanosky JD, Paciorek C, Schwartz J, Suh H, Speizer FE, Laden F. Chronic fine and coarse particulate exposure, mortality, and coronary heart disease in the Nurses' Health Study. Environ Health Perspect. 2009; 117:1697–1701.Google Scholar
    • 158 Peters A, Dockery DW, Muller JE, Mittleman MA. Increased particulate air pollution and the triggering of myocardial infarction. Circulation. 2001; 103:2810–2815.Google Scholar
    • 159 Sullivan J, Sheppard L, Schreuder A, Ishikawa N, Siscovick D, Kaufman J. Relation between short‐term fine‐particulate matter exposure and onset of myocardial infarction. Epidemiology. 2005; 16:41–48.Google Scholar
    • 160 Wang T, Lang GD, Moreno‐Vinasco L, Huang Y, Goonewardena SN, Peng YJ, Svensson EC, Natarajan V, Lang RM, Linares JD, Breysse PN, Geyh AS, Samet JM, Lussier YA, Dudley S, Prabhakar NR, Garcia JG. Particulate matter induces cardiac arrhythmias via dysregulation of carotid body sensitivity and cardiac sodium channels. Am J Respir Cell Mol Biol. 2012; 46:524–531.Google Scholar
    • 161 Pope CA, Dockery DW. Health effects of fine particulate air pollution: lines that connect. J Air Waste Manag Assoc. 2006; 56:709–742.Google Scholar
    • 162 Kloog I, Coull BA, Zanobetti A, Koutrakis P, Schwartz JD. Acute and chronic effects of particles on hospital admissions in New‐England. PLoS One. 2012; 7:e34664.Google Scholar
    • 163 Kunzli N, Jerrett M, Mack WJ, Beckerman B, LaBree L, Gilliland F, Thomas D, Peters J, Hodis HN. Ambient air pollution and atherosclerosis in Los Angeles. Environ Health Perspect. 2005; 113:201–206.Google Scholar
    • 164 Wellenius GA, Boyle LD, Wilker EH, Sorond FA, Coull BA, Koutrakis P, Mittleman MA, Lipsitz LA. Ambient fine particulate matter alters cerebral hemodynamics in the elderly. Stroke. 2013; 44:1532–1536.Google Scholar
    • 165 Du Y, Xu X, Chu M, Guo Y, Wang J. Air particulate matter and cardiovascular disease: the epidemiological, biomedical and clinical evidence. J Thorac Dis. 2016; 8:E8–E19.Google Scholar
    • 166 Nemmar A, Hoet PH, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, Vanbilloen H, Mortelmans L, Nemery B. Passage of inhaled particles into the blood circulation in humans. Circulation. 2002; 105:411–414.Google Scholar
    • 167 Martinelli N, Olivieri O, Girelli D. Air particulate matter and cardiovascular disease: a narrative review. Eur J Intern Med. 2013; 24:295–302.Google Scholar
    • 168 Steinvil A, Kordova‐Biezuner L, Shapira I, Berliner S, Rogowski O. Short‐term exposure to air pollution and inflammation‐sensitive biomarkers. Environ Res. 2008; 106:51–61.Google Scholar
    • 169 van Eeden SF, Tan WC, Suwa T, Mukae H, Terashima T, Fujii T, Qui D, Vincent R, Hogg JC. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM(10)). Am J Respir Crit Care Med. 2001; 164:826–830.Google Scholar
    • 170 Gurgueira SA, Lawrence J, Coull B, Murthy GG, Gonzalez‐Flecha B. Rapid increases in the steady‐state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation. Environ Health Perspect. 2002; 110:749–755.Google Scholar
    • 171 Magari SR, Schwartz J, Williams PL, Hauser R, Smith TJ, Christiani DC. The association between personal measurements of environmental exposure to particulates and heart rate variability. Epidemiology. 2002; 13:305–310.Google Scholar
    • 172 Pope CA, Burnett RT, Krewski D, Jerrett M, Shi Y, Calle EE, Thun MJ. Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: shape of the exposure‐response relationship. Circulation. 2009; 120:941–948.Google Scholar
    • 173 Sleiman M, Logue JM, Luo W, Pankow JF, Gundel LA, Destaillats H. Inhalable constituents of thirdhand tobacco smoke: chemical characterization and health impact considerations. Environ Sci Technol. 2014; 48:13093–13101.Google Scholar
    • 174 Zhang Y, Sumner W, Chen DR. In vitro particle size distributions in electronic and conventional cigarette aerosols suggest comparable deposition patterns. Nicotine Tob Res. 2013; 15:501–508.Google Scholar
    • 175 Manigrasso M, Buonanno G, Fuoco FC, Stabile L, Avino P. Aerosol deposition doses in the human respiratory tree of electronic cigarette smokers. Environ Pollut. 2015; 196:257–267.Google Scholar
    • 176 FDA . Vaporizers, e‐cigarettes, and other electronic nicotine delivery systems (ends). 2016.Google Scholar
    • 177 Suner IJ, Espinosa‐Heidmann DG, Marin‐Castano ME, Hernandez EP, Pereira‐Simon S, Cousins SW. Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 2004; 45:311–317.Google Scholar
    • 178 Tobacco Control Legal Consortium . U.S. E‐cigarette regulation: a 50‐state review. 2015.Google Scholar
    • 179 Sleiman M, Logue JM, Montesinos VN, Russell ML, Litter MI, Gundel LA, Destaillats H. Emissions from electronic cigarettes: key parameters affecting the release of harmful chemicals. Environ Sci Technol. 2016; 50:9644–9651.Google Scholar

    eLetters(0)

    eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

    Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.