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Public Health Consequences of E-Cigarettes (2018)

Chapter: 9 Cardiovascular Disease

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9 Cardiovascular Disease Active smoking of combustible tobacco cigarettes and exposure to secondhand tobacco smoke are established causes of clinical cardiovas- cular disease. Prior Surgeon General reports concluded that the evidence is sufficient to infer that active combustible tobacco cigarette smoking causes coronary heart disease, stroke, atherosclerotic peripheral artery disease, and aortic aneurysm and early abdominal aortic atherosclerosis, and that for secondhand tobacco smoke, the evidence is sufficient to infer that it causes coronary heart disease and stroke (HHS, 2014). Evidence on the cardiovascular effects of active smoking and cardiovascular disease is derived from multiple epidemiological and experimental studies, from studies showing the relatively short-term benefits on the cardiovascular system of quitting smoking, and from the reduction in cardiovascular hospitalizations following the implementation of smoke-free legislation in multiple countries and communities around the world. When evaluating the potential cardiovascular effects of e-cigarette use, it is important to consider what is known about the dose–response or the exposure–response relationship between exposure to airborne fine particulate matter and cardiovascular disease (Pope et al., 2009). Data combined from multiple studies to estimate adjusted relative risks of cardiovascular mortality plotted against the estimated average daily dose of fine particulate matter from combustible tobacco cigarette smoke, sec- ondhand tobacco smoke, and ambient air pollution showed that the expo- sure–response relationship between fine particulate matter and cardiovas- cular disease mortality is relatively steep at low levels of exposure and 339

340 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES it plateaus at higher levels. Because the particle characteristics and com- position of e-cigarettes differ from those emitted by combustible tobacco cigarettes (see Chapter 3), it is not possible to extrapolate at this time whether the ultrafine particles and liquid particles emitted by e-cigarettes are toxic to the cardiovascular system. The possibility that they could be toxic, however, makes research in this area very important. In addition to the particles, some toxicants in combustible tobacco cigarette smoke have been specifically related to cardiovascular disease risk, in particular metals, such as lead, nickel, and cadmium (Cosselman et al., 2015; Nigra et al., 2016). Because increasing evidence supports that e-cigarettes, particularly the heating coil, are a source of metals (see Chap- ter 5), the cardiotoxicity of e-cigarettes that use metallic coils to heat the e-liquid should be evaluated. Nicotine, moreover, as it has been reviewed in Chapter 4, stimulates the sympathetic nervous system, which results in short-term increases in heart rate, blood pressure, and myocardial con- tractility (see Figure 9-1). These nicotine mechanisms have been involved in the short-term effects of tobacco as a trigger for myocardial ischemia and myocardial infarction (HHS, 2014), although currently there is no consensus about the health effects of nicotine. While some investigators FIGURE 9-1 Conceptual framework of plausible pathways, including mecha- nisms and intermediate outcomes, by which exposure to e-cigarettes influences cardiovascular disease. SOURCE: Adapted from HHS, 2014.

CARDIOVASCULAR DISEASE 341 have minimized potential effects on cardiovascular disease (Benowitz and Fraiman, 2017), others see greater risk (Bhatnagar, 2016). Possible mecha- nistic pathways for particulates, metals, and other toxic chemicals, which are also found in e-cigarette aerosols and could thus be by which exposure to e-cigarettes influences cardiovascular disease related to atherosclerosis and coronary heart disease, are summarized in Figure 9-1. This figure is inspired from the well-established evidence of the toxicity of combus- tible tobacco products on the cardiovascular system, as summarized in the Surgeon General’s report (HHS, 2014). A major difference among the potentially cardiotoxic substances that are found in combustible tobacco cigarettes, but not in e-cigarettes, is the lack of combustion chemicals such as polycyclic aromatic hydrocarbons and carbon monoxide (see Chapter 5). The possibility that e-cigarettes may increase the risk of cardiovascular disease must be evaluated carefully given the high burden of cardiovas- cular disease worldwide and the importance of the burden of disease in the estimation of attributable risk. CHARACTERIZATION OF DISEASE ENDPOINTS AND INTERMEDIATE OUTCOMES Relatively few studies have investigated the cardiovascular effects of e-cigarette products. In particular, there are no epidemiological studies evaluating clinical outcomes such as coronary heart disease, stroke, or atherosclerotic peripheral artery disease, or established subclinical out- comes of underlying atherosclerosis such as carotid intima-media thick- ness or coronary artery calcification. Clinical outcomes such as coronary heart disease (including myocardial infarction and sudden cardiac death), stroke, and peripheral artery disease have been the cornerstone of pro- spective epidemiological studies evaluating the vascular effects of com- bustible tobacco cigarettes. Subclinical measures of atherosclerosis, such as carotid intima-media thickness or coronary artery calcification, are also considered excellent measures of cardiovascular risk that can inform on relevant mechanistic pathways (see Figure 9-1). Importantly, these can be measured in cross-sectional designs, allowing for some early assessment as compared with the long-term follow-up needed for clinical cardiovas- cular outcomes. None of the studies on e-cigarettes and cardiovascular disease conducted so far and summarized below, however, have mea- sured either clinical cardiovascular outcomes or subclinical atherosclerotic outcomes. This lack of data on e-cigarettes and clinical and subclinical atherosclerotic outcomes represents a major research need. Conclusion 9-1. There is no available evidence whether or not e-cigarette use is associated with clinical cardiovascular outcomes (coro-

342 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES nary heart disease, stroke, and peripheral artery disease) and subclini- cal atherosclerosis (carotid intima-media thickness and coronary artery calcification). The evidence available on the possible cardiovascular effects of e-cigarettes can be classified as studies conducted in vitro, evaluating the cytotoxicity of e-cigarette aerosols and other alterations in myocardial cells and human vascular cells; studies conducted in vivo, evaluating relevant mechanistic pathways for cardiovascular toxicity in mice; and clinical experiments, generally crossover experiments that have assessed short-term cardiovascular effects, such as changes in heart rate, blood pressure, and arterial stiffness, of e-cigarettes as compared with combus- tible tobacco cigarettes and to not smoking. A few studies have evaluated the associations between e-cigarette use and heart rate, heart rate vari- ability, blood pressure levels, and markers of oxidative stress over longer periods, including a cohort study of patients with hypertension who were using e-cigarettes (Polosa et al., 2016), a randomized clinical trial evaluat- ing the effect of switching from smoking to e-cigarette use analyzed also as a cohort study (Farsalinos et al., 2016), and a cross-sectional study com- paring heart rate variability and oxidative stress measures in e-cigarette users versus non-users (Moheimani et al., 2017). Heart rate, controlled by the autonomic nervous system, is a power- ful measure of cardiovascular function (Koskela et al., 2013; Poirier, 2014). Slower average resting heart rate is related to higher cardiovascular health and longer life span. Endurance physical exercise can reduce resting heart rate and promote cardiovascular health. The increase in cardiovascular risk associated with high resting heart rate maybe due to elevated blood pressure or sympathetic overactivity (Koskela et al., 2013). Elevated bra- chial blood pressure is one of the best established contributors to clinical cardiovascular disease and mortality, including myocardial infarction, stroke, and renal failure, when not detected early and treated appropri- ately (James et al., 2014). Hypertension diagnosis, treatment, and control are critical for cardiovascular disease prevention and control. Hyperten- sion can be defined when either systolic or diastolic blood pressure (SBP or DBP) is elevated. While there are blood pressure cutoffs that are used clinically, the increase in cardiovascular risk is continuous along blood pressure levels. The short-term effects of combustible tobacco cigarettes on both heart rate and blood pressure levels are well established, result- ing in short-term elevations that could be related to the effects of nico- tine. Long term, however, the effect of combustible tobacco cigarettes on both heart rate and brachial blood pressure levels are less clear, although chronic smoking has been associated with elevated central systolic blood pressure in smokers (Mahmud and Feely, 2003). The short-term effects of

CARDIOVASCULAR DISEASE 343 smoking in heart rate and brachial blood pressure could also play a role in triggering acute events. Arterial elasticity is essential for blood flow, and the hardening or stiffening of the arteries plays an important role in the development of cardiovascular disease. Arterial stiffness, which can be also defined as arteriosclerosis, or the hardening of the artery wall, can be assessed non-invasively measuring the pulse wave velocity, which measures the speed of the blood pressure wave along the arte- rial system. Pulse wave velocity can be measured at the carotid, aortic, or brachial levels and it is a strong predictor of clinical cardiovascular events (Mattace-Raso et al., 2006; Willum Hansen et al., 2006). Combus- tible tobacco cigarette smoking has been associated with arterial stiffness both in short-term experiments and in studies evaluating chronic effects (Levenson et al., 1987; Mahmud and Feely, 2003). In healthy individu- als without established cardiovascular disease or major cardiovascular risk factors, endothelial function is also related to increased arterial stiff- ness. Because endothelial function is an early marker of atherosclerosis (narrowing of the arteries because of the presence of plaque) and clini- cal cardiovascular disease characterized by a reduced bioavailability of endothelium-derived nitric oxide (NO), it shows the close interrelated- ness between these well-established markers of cardiovascular disease (McEniery et al., 2006). In the sections below, the committee reviews the clinical experiments evaluating the short-term cardiovascular effects of e-cigarettes as well as the few studies that have evaluated the effects of e-cigarettes on the cardiovascular system over longer periods of time or in a cross-sectional setting. The primary focus of this chapter is understanding the cardiovas- cular effects of e-cigarettes compared with no use, although we also report on findings compared with combustible tobacco cigarettes when those are available in the studies evaluated. A more detailed comparison of the cardiovascular effects of e-cigarettes versus combustible tobacco cigarettes is found in Chapter 18 on harm reduction. In the absence of clinical or subclinical studies on the long-term cardiovascular effects of e-cigarettes, evaluating the potential harm reduction of e-cigarettes is preliminary. EVIDENCE FROM HUMAN STUDIES OF CARDIOVASCULAR EFFECTS A total of 13 clinical intervention studies published between 2010 and 2017 have evaluated acute cardiovascular effects of e-cigarette use, such as changes in blood pressure levels, heart rate, arterial stiffness and endothelial function, cardiac geometry and function, and oxidative stress measured in minutes to hours following the intervention (see Table 9-1). Among them, 11 studies were crossover studies in which all participants

344 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1  Clinical Studies of Short-Term Effects of E-Cigarette Use on Cardiovascular Endpoints Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid St.Helen et Not blinded, Healthy sole and 32.3 years KangerTech al., 2017 3-arm dual e-cigarette 79% Mini ProTank 3 randomized user (≤5 cigarettes 14.3% clearomizer (1.5 crossover per day) from 71.4% Ω) connected to a trial over 3 colleges campuses 0% KangerTech 3.7-V, consecutive in San Francisco, 1,000-mAh battery; days (in- CA 3 flavors: Bulk patient) e-liquid strawberry (pH 8.29) Bulk e-liquid tobacco (pH 9.10) Own flavor (mean pH 6.80) with 50/50 PG/glycerol and 18 mg/ml nicotine (for strawberry and tobacco) Spindle et al., Not blinded, Healthy sole 29.6 years Own e-cigarette 2017 2-arm ordered and dual 76% device and e-liquid crossover e-cigarette users 7% (≥12 mg/ml nicotine) trial with a (≤5 combustible NR minimum tobacco cigarettes 0% of 48-hour per day) from washout Richmond, VA, period using e-cigarettes for at least 3 months

CARDIOVASCULAR DISEASE 345 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results Ad libitum Before and at 5, 14 HR (bpm) Mean max change (SEM) (ad lib) 10, 15, 20, and in HR after 15 puffs versus acclimatization 30 minutes after baseline was: from 4 to 10 the final puff of: 17.2 (2.5) (strawberry), pm, abstinent Strawberry 12.3 (2.3) (tobacco), overnight, 15 Tobacco 9.4 (2.4) (own flavor). puffs/session Own flavor Mean maximum increase (1 every 30 (95% CI) was 4.6 (0.8, 8.5) seconds) followed bpm higher for strawberry by 4 hours of e-liquid than for tobacco abstinence, and e-liquid. then 90 minutes Mean (SEM) of HR area ad lib. under the curve (AUC) Mean max after 15 puffs was nicotine 245 (37) (strawberry), concentration 210 (45) (tobacco), (SEM) was 12.1 169 (53) (own flavor). (2.0), 9.5 (1.2) and Mean difference (95% CI) 6.2 (1.0) ng/ml in HR AUC: 34 (−43, 111) for strawberry, comparing strawberry to tobacco, and tobacco. own flavor, No difference in HR by pH respectively. of the e-liquid, mean (SEM) 183 (85) versus 154 (69) for usual acidic and usual basic pH (p = 0.85). HR not reported for the ad lib session. 10 puffs, 30- Before and 29 HR (bpm) Mean (SEM) HR increased second interpuff continually to 73.3 (1.3) bpm after interval, and every 20 the directed bout and to 90-minute ad lib seconds for 73.9 (1.5), 73.6 (1.6), and bout. 2.5 hours 74.4 (1.7) at 30, 60, and 90 Plasma nicotine comparing same minutes, respectively, after increased up to device and the onset of the ad lib but 4.6 ng/ml during e-liquid with compared with baseline of ad lib. or without a 66.3 (1.3) bpm. mouthpiece continued

346 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid St.Helen et 1-arm trial Healthy sole and 38.4 years Usual brand of al., 2016 dual e-cigarette 54% device and e-liquid users (≤5 cigarettes 23% per day) NR 0% Carnevale et Single blinded Healthy smoking 28.0 years NR leading brand al., 2016 2-arm ordered and never smoking 47.5% charged; crossover trial participants 50% 16-mg nicotine with 1-week from Rome, Italy 0% cartridge (~250 puffs) washout (recruitment dates NR NR)

CARDIOVASCULAR DISEASE 347 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results 15 puffs/session, Before and 5, 13 HR (bpm) Compared with baseline 30-second 10, 15, 20, and HR increased a mean of interpuff interval, 30 minutes after 8.0 (p < 0.001) and 5.2 (p followed by the final puff = 0.04) bpm after 5 and 4 hours of 10 minutes, respectively, abstinence, and and was not significantly then 90 minutes different after 15 minutes. ad lib. Mean plasma nicotine after 15 puffs was 8.4 ng/ ml. 1 cigarette, Just before and 40 Serum sNOX2- Mean (SD) before and 9 puffs 30 minutes after dp (pg/ml), after combustible tobacco (equivalent to 0.6 - 1 combustible 8-iso-PGF2α cigarette/e-cigarette mg of nicotine). tobacco (pmol/L), 23.6 (7.8) 38.2 (9.9)/21.6 Cotinine NR. cigarette Serum NO (µM), (6.8) 30.2 (6.2) - 9 e-cigarette Serum vitamin E 135 (56) 203 (81)/133 (54) puffs (µmol/mmol), 187 (62) Brachial artery 35.3 (12.0) 19.5 (9.9)/35.5 FMD (%) (12.5) 25.9 (12.1) 4.6 (1.8) 3.1 (1.9)/3.8 (1.6) 2.8 (1.2) 6.7 (4.3) 3.4 (3.9)/6.7 (3.6) 4.3 (2.2) Stratified results for smokers and non-smokers similar with worse profile for smokers. continued

348 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid Antoniewicz Single Healthy sporadic 28 years eGo XL (2nd- et al., 2016 blinded 2-arm smokers from 64.3% generation), 1,100- randomized Stockholm, Sweden, 100% mAh, 3.7-V, dual-coil crossover trial not smoking in 0% CE5 atomizer. with 1-week the last 7 days 100% E-liquid with washout (recruitment dates nicotine 12 mg/ml, NR) 44.4/49.4% PG/glycerol without flavors (Valeo laboratories GmbH).

CARDIOVASCULAR DISEASE 349 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results 10 puffs in Before and 1, 16 EPC (leukocytes, EPCs increased after 10 minutes in 4, and 24 hours events) e-cigarette use at 1 hour semisupine after: Microvesicles (p = 0.003) and 4 hours position. - E-Cigarette (number) all (p = 0.036) and returned Median (IQR) - Control and by origin to normal at 24 hours. No plasma cotinine (resting) (endothelial, changes were observed for after 4 hours was platelet or control periods. 4.1 (3.5, 4.7) leukocytes) and Median (IQR) pre, 1, 4, 24 ng/ml. inflammation hours e-cigarette/control markers 1,725 (731, 4,012), 2,600 (HMGB1, (1,264, 7,668), 5,102 (2,164, P-selectin, CD40, 7,858), 5,731 (1,402, 7,176)/ and E-selectin 1,557 (1,020, 4,997), 3,277 [CD62E]) (2,038, 4,987), 3,700 (2,545, FeNO (only pre 4,494), 2,724 (2,012, 4,858) and 24 hours) p = 0.683. NS associations for MVs by origin and inflammation markers except for E-selectin: 8 (2, 17), 14 (8, 43), 28 (17, 65), 20 (15, 40)/ 9 (4, 22), 19 (12, 40), 23 (14, 42), 23 (11, 37) (p = 0.038). Median (IQR) pre, 24 hours e-cigarette/controls 10 (7, 15), 11 (8, 14)/ 10 (7, 15), 11 (8, 14), p = 0.88. continued

350 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid Fogt et al., Double Healthy 23.1 (±2.5) GreenSmartLiving 2016 blinded, participants from years e-cigarette (details 2-arm ordered San Antonio, TX 50% not described). crossover trial (recruitment dates 0% E-liquid with 0 and with 1-week NR) NR 18 mg/ml nicotine. washout 100% Cooke et al., Double Healthy non- 23 (±1) years GreenSmartLiving 2015 blinded, smoking 50% e-cigarette (details randomized, participants from 0% not described). 2-arm San Antonio, TX NR E-liquid with 0 and crossover trial (recruitment dates 100% 18 mg/ml nicotine. with 1-week NR) washout

CARDIOVASCULAR DISEASE 351 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results 20 puffs in 10 40 minutes 20 Resting: Mean (SD) 0/18 mg/ml minutes inhaling post-exposure: SBP (mmHg) e-cigarette as deeply as - E-cigarette 0 DBP (mmHg) 115.8 (8.0)/112.1 (6.8), possible. mg/ml HR (bpm) p = 0.04 Urine cotinine - E-cigarette 18 RMR (kcal/min) 73.6 (8.3)/76.6 (6.0), 0–10 and 30–100 mg/ml VO2 (L/min) p = 0.04 ng/ml for 18 Exercise RQ (energy exp.) 61 (10)/61 (10), p = 0.47 and 0 mg/ test starts Exercise test: 1.19 (0.2)/1.18 (0.2), p = ml e-cigarette, 55 minutes SBPpeak (mmHg) 0.39 respectively. post–e-cigarette DBPpeak (mmHg) 0.25 (0.1)/0.25 (0.2), p = 0.5 exposure (VO2)peak 0.79 (0.01)/0.78 (0.1), (L/min) p = 0.15 Power (W)peak Numbers NR, p = 0.14 74.9 (8.3)/79.4 (7.6), p = 0.02 2.3 (0.7)/2.3 (0.8), p = 0.77 204.8 (57.8)/201.0 (53.8), p = 0.29 20 puffs in 10 Before and 20 Seated: Change pre-post 0/18 minutes. 10–20 (seated), SBP (mmHg) mg/mlb Urine cotinine 20–25 (supine), DBP (mmHg) −2/2 (p ≤ 0.03) 0–10 and 30–100 25–30 (70° head- HR (pbm) −2/4 (p = 0.001) ng/ml for 18 up tilt), and Supine, tilt, −4/1.2 (p ≤ 0.03) and 0 mg/ 30–35 (supine) and recovery Mean BP in each position ml e-cigarette, minutes post- positions (5 0/18 mg/mlb respectively. exposure: minutes each): 109/117 p = NR, 99/108 - E-cigarette SBP (mmHg) (p = 0.03), 110/118 (p = NR) 0 mg/ml DBP (mmHg) 62/69 (p = 0.02), 61/67 - E-cigarette Autonomic (p = 0.02), 64/71 (p = 0.04). 18 mg/ml control: R-R and RRISD decreased 1-week washout R-R with tilt (p ≤ 0.01), but period RRISD reductions were similar by treatment group. continued

352 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid Yan and Single Healthy 38.7 years blu e-cigarettes with D’Ruiz, 2015 blinded, participants 48% the following e-liquid randomized smoking in past 100% formulations: 6-arm 12 months from 0% A: classic e-cigarette crossover trial Lincoln, NE, and 0% 2.4% nicotine 75% with 36-hour after a lead-in glycerol washout period for 7 days B: classic e-cigarette period to get accustomed 2.4% nicotine 50/20% to using e-cigarette glycerol/PG products and C: menthol abstaining from e-cigarette, 2.4% nicotine for 36 nicotine 75% glycerol hours D: classic e-cigarette 1.6% nicotine 75% glycerol E: classic e-cigarette 1.6% nicotine 50/20% glycerol/PG Szołtysek- Single Healthy students 23 (±2) years Ego-3 (clearomizer Bołdys et al., blinded, 2-arm of University of 0% Crystal 2 with coil, 2014 ordered cross- Silesia, Poland, 100% 2.4-Ω voltage battery over trial with smoking >5 0% 900-mAh, 3.4-V) 1-day washout cigarettes per day 0% nicotine 24 mg/ml period for 2 years and used e-cigarettes at least 10 times

CARDIOVASCULAR DISEASE 353 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results E-cigarette: 50 30 minutes pre 23 SBP (mmHg) Change (SD) post versus 5-second puffs and 20 minutes DBP (mmHg) pretreatment: at 30-second following the HR (bpm) A: 1.1 (11.1), p = 0.63/ intervals. end of the ad B: 2.8 (11.3), p = 0.24/ Combustible lib period of C: 4.0 (10.0), p = 0.07/ tobacco cigarette: e-cigarette A, D: 5.8 (10.0), p = 0.02/ usual puff B, C, D, E, and E: 3.8 (10.7), p = 0.10/ duration at 30- F (Marlboro F: 5.7 (12.4), p = 0.04. second intervals. cigarette) A: 6.8 (6.7), p < 0.001/ E-cigarette and B: 6.8 (6.5), p < 0.001/ combustible C: 3.2 (7.3), p = 0.05/ tobacco cigarette: D: 6.8 (3.8), p < 0.001/ 1 hour ad lib use. E: 4.4 (4.7), p < 0.001/ Plasma nicotine F: 6.8 (7.1), p < 0.001. (ng/ml) ranged A: 2.3 (5.5), p = 0.06/ from 2.0 (D) to 3.0 B: 3.6 (6.0), p = 0.008/ (B) at 5 minutes, C: 4.1 (5.7), p = 0.002/ from 10.0 (D) D: 1.9 (7.4), p = 0.24/ to 17.1 (B) at 30 E: 2.2 (5.9), p = 0.08/ minutes and from F: 4.3 (5.4), p = 0.001. 13.7 (D) to 22.4 Plasma nicotine positively (B) after 1 extra correlated with HR change hour ad lib. For with a mean increase of cigarettes, it was 0.16 bpm for 1 ng/ml 14.4, 7.9, and 29.2 increase in plasma nicotine at the same times. (R2: 0.64). 1-hour sessions: 10 minutes 15 Arterial stiffness: Mean (95% CI) before and Combustible after: SI (m/s) after cigarette/e-cigarette tobacco cigarette - Combustible RI (%) SI: 6.75 (6.66, 6.85), 6.56 10–12 puffs tobacco cigarette SBP (mmHg) (6.46, 6.65), p = 0.006/ (personal brand) - E-Cigarette DBP (mmHg) 6.73 (6.62, 6.84), 6.75 (6.66, E-Cigarette 15 HR (bpm) 6.83) p = NS. puffs RI: 54.0 (51.5, 56.7), 49.6 Cotinine NR (47.5, 51.8), p = 0.01/ 52.0 (49.3, 54.7), 50.8 (48.2, 53.3), p = NS. Both cigarettes and e-cigarette showed a small increase in SBP, DBP, and HR, but it was not significant (only figure) and was hard to see. continued

354 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid Farsalinos et Not blinded, Healthy 35 (±5) years eGO-T battery al., 2014 2-arm ordered consecutive 90% (Nobacco, Greece) trial with no smokers at Onassis 47% with an eGo-C smoking or Cardiac Surgery 53% atomizer (2nd nicotine use Center, Greece (>14 NA generation) 650- in the 4 hours cigarettes per day mAh rechargeable before the for ≥5 years) and lithium battery, 3.5 V, intervention e-cigarette users manually activated who quit smoking 11 mg/ml nicotine and used 9–12 mg/ PG >60%, linalool ml nicotine e-liquid <5%, tobacco essence for ≥1 month (mean <5%, methyl vanillin 6 months). Smokers <1%. and e-cigarette users similar at baseline except e-cigarette users formerly smoked 10 combustible tobacco cigarettes per day more when they smoked than current smokers

CARDIOVASCULAR DISEASE 355 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results Combustible Before and after 36 SBP (mmHg) Mean (SD) change before tobacco cigarette the experiments 40 DBP (mmHg) after cigarette/e-cigarette smoked ad lib. - Combustible HR (bpm) Before: 6.6 (5.2) p < E-cigarette ad lib tobacco Echocardiography 0.001/0.7 (4.6) p = 0.37 for 7 minutes. cigarette E (cm/s) After: 4.4 (3.3) p < 0.001/3.0 Cotinine NR. smokers A (cm/s) (3.6) p < 0.001 Experiments for - E-cigarette E/A 5.9 (4.7) p < 0.001/0.4 (4.8) e-cigarette and users DT (ms) p = 0.649 combustible IVRT (ms) −0.6 (6.1) p = 0.57/1.2 (5.0) tobacco cigarettes IVRTc (ms) p = 0.13 were done in MPI 2.9 (5.7) p = 0.007/1.6 (5.6) different rooms. Sm (cm/s) p = 0.08 Em (cm/s) −0.10 (0.16) p = 0.001/−0.03 Am (cm/s) (0.14) p = 0.17 Em/Am 3 (10) p = 0.09/1 (8) p = E/Em 0.58 MPIt 5.6 (9.2) p < 0.001/−1.0 (5.7) GS (%) p = 0.28 SRs (s-1) 10.4 (10.1) p < 0.001/−1.2 SRe (s-1) (6.9) p = 0.29 SRa (s-1) 0.03 (0.04) p = 0.002/−0.01 (0.04) p = 0.330 −0.8 (1.1) p = 0.57/0.2 (0.7) p = 0.17 −0.7 (1.4) p < 0.001/0.2 (0.7) p = 0.10 0.1 (0.6) p = 0.80/0.2 (0.8) p = 0.12 −0.08 (0.13) p = 0.004/−0.01 (0.13) p = 0.54 0.29 (0.74) p = 0.02/0.01 (0.47) p = 0.87 0.03 (0.05) p = 0.004/−0.01 (0.04) p = 0.08 0.2 (1.7) p = 0.441/−0.4 (1.2) p = 0.06 −0.2 (0.1) p = 0.15/−0.01 (0.07) p = 0.36 –0.08 (0.12) p < 0.001/0.01 (0.08) p = 0.35 0.03 (0.09) p = 0.11/0.01 (0.08) p = 0.462 (continues on p. 357) continued

356 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid Czogała et Not blinded, Healthy daily 34.9 (15.3) MILD M2001 (1st al., 2012 2-arm ordered cigarette smokers years generation); 14 mg/ crossover (≥5 cigarettes 50% ml nicotine study with per day) from 100% 1-week Sosnowiec, Poland 0% L&M blu label PM washout 100% cigarette Eissenberg, Not blinded, Healthy smokers 29.8 years NPRO (NJOY) and 2010 4-arm ordered from Richmond, 69% Hydro (Crown Seven) trial with VA, with 12 100% 16-mg nicotine washout hours of tobacco/ 0% cartridge menthol or period of 48 nicotine abstinence 100% non-menthol (choice hours confirmed with of participant) CO <10 ppm

CARDIOVASCULAR DISEASE 357 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results (continued from p. 355) Also run analysis for the effect of combustible tobacco cigarette versus e-cigarette on changes of echocardiographic measures after adjustment for changes in SPB and HR (IVRT, IVRTc, MPI, Em, MPIt, SRe remained significantly associated). Ad lib e-cigarette - Combustible 42 SBP (mmHg) Mean (SD) before and use (minimum tobacco DBP (mmHg) after combustible tobacco amount of puffs cigarette HR (bpm) cigarette/e-cigarette NR) - E-cigarette SBP: 127.1 (15.4) to 131.4 (NS)/122.6 (11.4) to 122.5 (12.6) (NS) DBP: 78.8 (11.0) to 84.1 (10.4) (p = 0.02)/76.7 (9.5) to 78.6 (10.8) (NS) HR: 78.5 (12.0) to 90.9 (15.4) (p < 0.001)/77.9 (79.4) to 79.4 (13.6) (NS) Instructed to Before and up 16 HR (bpm) HR increased only after puff and then to 30 minutes own cigarette (p < 0.05). puffed ad lib 10 after 1st puff: Numbers are not shown times (30-second Cigarette (own) in the paper for either intervals) for each Sham puffing combustible tobacco product, cycle NPRO cigarette or e-cigarette. was repeated 60 Hydro minutes later. Plasma nicotine (ng/ml) for own cigarette, NPRO, and Hydro, respectively, were 16.8, 3.5, and 2.5 at 5 minutes and 8.7, 2.6, and 2.2 at 30 minutes continued

358 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-1 Continued Mean Age % Men % C-Smoker % F-Smoker E-Cigarette Device % Naïve Characteristics and Reference Study Design Population E-Cigarette E-Liquid Vansickel et Not blinded, Healthy smokers 33.6 years NPRO (18 mg, NJOY) al., 2010 randomized from Richmond, 59% Hydro (16 mg) 4-arm trial VA, with 12 100% with washout hours of tobacco/ 0% period of ≥48 nicotine abstinence 100% hours confirmed with CO < ppm a Final sample size used in the analyses. For Antoniewicz and colleagues (2016), 2 partici- pants were excluded from the 16 initially recruited because cotinine levels were compatible with recent smoking. For Yan and D’Ruiz (2015), initially 38 participants were recruited but only 23 participants completed the study. b Numbers approximated because abstracted from a figure. NOTES: 8-iso-PGF2α = 8-iso-prostaglandin F2α; EPC = endothelial progenitor cells; FMD = flow-mediated dilation; HR = heart rate; LA = left atrial; LV = left ventricle; MSNA = efferent received 2 or more interventions (in 6 of them the order of the interven- tion was randomized) (Antoniewicz et al., 2016; Cooke et al., 2015; Fogt et al., 2016; St.Helen et al., 2017; Vansickel et al., 2010; Yan and D’Ruiz, 2015), and in the other 5, the order was preassigned and the same for everybody (Carnevale et al., 2016; Czogała et al., 2014; Eissenberg, 2010; Spindle et al., 2017; Szołtysek-Bołdys et al., 2014). The remaining studies were a two-arm design to evaluate the short-term effect of smoking a cigarette and of vaping an e-cigarette in smokers and previous users of e-cigarettes, respectively (Farsalinos et al., 2014) and a single-arm before/ after trial (St.Helen et al., 2016).

CARDIOVASCULAR DISEASE 359 Intervention Pattern and Comparison Cotinine Levels Groups na Study Endpoints Results Instructed to Before and up 32 HR (bpm) HR increased from 66 ppm puff 10 times to 1 hour after: before the experiment to 80, with 30-second - Combustible 75, and 70 ppm 5, 15, and intervals at 2 tobacco 30 minutes, respectively, separate times cigarette (own) after the first experiment during the - Sham puffing and to 74, 73, and 70 ppm session (1 hour - NPRO after the second experiment between them). - Hydro with the own-brand Plasma nicotine cigarette. For NPRO and increased for Hydro, only small changes own brand but not statistically significant not for NPRO, were observed (from 66 Hydro, and sham ppm before to a maximum experiments. of 69 ppm at 5 minutes after the first experiment and 67 ppm at 5 minutes after the second experiment with NPRO; and even smaller changes with Hydro). muscle sympathetic nerve activity from the right peroneal nerve; NA = not applicable; nic. = nicotine, NO = nitric oxide; NR = not reported; NS = not significant; Ox = oxidative; PG/ VG = propylene glycol/glycerol; RI = reflection index; RMR = resting metabolic rate; R-R = intervals to assess vagal-cardiac control in the time domain; RRISD = R-R interval standard deviations to assess respiratory sinus arrhythmia, SI = stiffness index; sNOX2-dp = soluble NOX2-derived peptide, a marker of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase activation. The literature search also identified 3 studies evaluating cardiovascular- related outcomes over a longer period than the 13 acute clinical stud- ies (see Table 9-2), including a cross-sectional study of e-cigarette users compared with non-users conducted in Los Angeles, California (n = 34) (Moheimani et al., 2017); a cohort of smokers not intending to quit from Catania, Italy, who were randomized to one of three types of e-cigarette use (0 percent nicotine, 2.4 percent nicotine for 12 weeks, and 2.4 percent nicotine for 6 weeks plus 1.8 percent nicotine for 6 weeks) (n = 183 with complete follow-up) and also analyzed as a cohort study comparing sole e-cigarette users (called quitters in the original publication), dual users

360 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES (called reducers), and smokers (called failures) according to their con- tinuation of combustible tobacco smoking (n = 145 for participants with continuous e-cigarette/smoking status over time) (Farsalinos et al., 2016); and a cohort of hypertensive patients who were e-cigarette users com- pared with hypertensive patients who smoked cigarettes (n = 89) also in Catania, Italy (Polosa et al., 2016). The sample size across the 15 studies ranged from 13 (St.Helen et al., 2016) to 183 (Farsalinos et al., 2016) participants, for a total of 662 partici- pants across the 15 studies (356 in the short-term clinical studies and 306 in the epidemiological studies). Study participants were recruited from Catania (Italy), Khallithea (Greece), Los Angeles (­ alifornia), Lincoln C (Nebraska), Richmond (Virginia), Rome (Italy), San Antonio (Texas), San Francisco (California), Silesia (Poland), Sosnowiec (Poland), and Stockholm (Sweden). In the short-term clinical studies, participants were relatively young (mean age ranged from 23 to 39 years old), required to be healthy (including no hypertension or diabetes risk factors in most s ­ tudies), and included a balanced number of men and women, except in one study restricted to women (Szołtysek-Bołdys et al., 2014) and another study that included 90 percent men (Farsalinos et al., 2014). Mean age of the participants in the epidemiological studies ranged from 33 to 54 years. In one study, all participants had hypertension at baseline. In a total of seven studies, all participants were current smokers (Antoniewicz et al., 2016; Czogała et al., 2014; Eissenberg, 2010; Farsalinos et al., 2016; Szołtysek-Bołdys et al., 2014; Vansickel et al., 2010; Yan and D’Ruiz, 2015), ranging from sporadic smokers to heavy smokers; five studies included some current smokers; and the remaining were former smokers (Farsalinos et al., 2014; St.Helen et al., 2017) or it was not specified if they were former or never smokers (Polosa et al., 2016; Spindle et al., 2017; St.Helen et al., 2016); one study included half of the participants being current smokers and half never smokers (Carnevale et al., 2016); one study included 65 percent never smokers and 35 percent former smokers; and in two studies the participants were not current smokers, although it is unclear if former smokers were included (Cooke et al., 2015; Fogt et al., 2016). Among the short-term clinical studies, in six studies the partici- pants were e-cigarette–naïve users (Antoniewicz et al., 2016; Cooke et al., 2015; Czogała et al., 2012; Eissenberg, 2010; Fogt et al., 2016; Vansickel et al., 2010); in one study participants were trained to use e-cigarettes during a 7-day period (Yan and D’Ruiz, 2015); in five studies participants were experienced e-cigarette users (Farsalinos et al., 2014; Szołtysek-Bołdys et al., 2014); and one study did not report whether participants were naïve e-cigarette users (Carnevale et al., 2016). The e-cigarette device used in the experiments included a tank-style device in one study (St.Helen et al., 2017); second-generation devices

CARDIOVASCULAR DISEASE 361 in three studies (different eGO models) (Antoniewicz et al., 2016; F ­ arsalinos et al., 2014; Szołtysek-Bołdys et al., 2014); cigalikes in six stud- ies (GreenSmartLiving in two studies [Cooke et al., 2015; Fogt et al., 2016]; blu in one study [Yan and D’Ruiz, 2015]; Mild in one study [Czogała et al., 2012]; NJOY NPRO and Hydro in two studies [Eissenberg, 2010; Vansickel et al., 2010]); one leading brand of an unspecified device in one study (Carnevale et al., 2016); and the personal devices of the study participants in two studies (Spindle et al., 2017; St.Helen et al., 2016). Nicotine or coti- nine biomarkers were reported in 10 studies and were generally lower than those that would be reached with combustible tobacco cigarettes (Antoniewicz et al., 2016; Cooke et al., 2015; Eissenberg, 2010; Fogt et al., 2016; Yan and D’Ruiz, 2015), except maybe for studies using tank-style devices and the personal e-cigarettes of the participants (Spindle et al., 2017; St.Helen et al., 2016, 2017). Few studies provided details on actual wattage and resistance (Antoniewicz et al., 2016; Farsalinos et al., 2014; ­ St.Helen et al., 2017; Szołtysek-Bołdys et al., 2014) and no ­ tudies provided s details on the coils. The e-liquid concentration of nicotine ranged from 0 mg/ml (Cooke et al., 2015; Fogt et al., 2016) to 24 mg/ml (Szołtysek- Bołdys et al., 2014), although some studies reported the total amount of nicotine in the cartridge, but not the actual concentration (Carnevale et al., 2016; Eissenberg, 2010). Only one study tested multiple propylene glycol (PG)/glycerol concentrations (Yan and D’Ruiz, 2015), and only two other s ­ tudies actually reported the concentrations of other constituents beyond nicotine (Antoniewicz et al., 2016; Farsalinos et al., 2014). Regarding fla- vors, only one study used a vanillin flavor (Farsalinos et al., 2014); two studies mentioned menthol, one allowing the choice of a menthol flavor- ing (Eissenberg, 2010), and another study specifically tested menthol (Yan and D’Ruiz, 2015); and one study compared strawberry flavor, tobacco fla- vor, and the personal flavor used by the participant (St.Helen et al., 2017). The interventions tested were substantially different across the short- term clinical studies. Seven studies compared the short-term effects of one or more e-cigarettes versus combustible tobacco cigarettes (Carnevale et al., 2016; Czogała et al., 2012; Eissenberg, 2010; Farsalinos et al., 2014; Szołtysek-Bołdys et al., 2014; Vansickel et al., 2010; Yan and D’Ruiz, 2015) (one of those also included one arm with sham puffing [Eissenberg et al., 2010]). One study compared e-cigarettes to a resting period in the same conditions as the e-cigarette use period (Antoniewicz et al., 2016). Two studies compared the same e-cigarette with e-liquids with and without nicotine (Cooke et al., 2015; Fogt et al., 2016) and with different flavors. One study compared the same e-cigarette and e-liquid with and with- out a mouthpiece (Spindle et al., 2017). The washout periods ranged from less than 24 hours (St.Helen et al., 2017) to 1 week in crossover s ­ tudies (Antoniewicz et al., 2016; Carnevale et al., 2016; Cooke et al., 2015;

362 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-2  Epidemiological Studies on Chronic E-Cigarette Use and Cardiovascular Endpoints Age Range E-Cigarette % Men E-Cigarette Pattern of Use Study % C-Smoker Device and Cotinine Reference Design Population % F-Smoker Characteristics Levels Moheimani et XS Los Angeles, 21–45 years NR Mean = 241 al., 2017 CA, recruited 59% minutes per day in 2015–2016 0% Mean = 1.6 (source or 35% years recruitment Plasma cotinine methods NR) range = 2.6–27.3 mg/L

CARDIOVASCULAR DISEASE 363 Comparison Study Groups na Endpoints Results Adjustmentb - E-cigarette 16/18 SBP (mmHg) Mean user/non-user 115.8/109.0 None users 12/18 DBP (mmHg) (p = 0.07) (e-cigarette - Non-users MAP (mmHg) 73.5/70.0 (p = 0.27) users more E-cigarette HR (bpm) 87.6/83.0 (p = 0.15) likely to users asked HRV: HF 64.0/63.0 (p = 0.73) be men not to use the (non-user) 46.5/57.8 (p = 0.04) and former e-cigarette -  F (non- L 52.7/39.9 (p = 0.03) smokers) the day of the user) 1.37/0.85 (p = 0.05) study -  F/HF L NS (no. not shown) HRV- 3,801/2,413 (p = 0.01) controlled 649.9/892.8 (p = 0.17) breathing 0.42/0.38 (p = 0.55) oxLDL (user) 270.9/251.9 (p = 0.24) paraxonase-1 3/1 (p = 0.15) (nmol) Correlations of plasma cotinine HDLantiox. with: index (user) HF (−0.34, p = 0.04) Fibrinogen LF (0.35, p = 0.03) (mg/dl) LF/HF (0.36, p = 0.03) CRP (number oxLDL (0.35, p = 0.05) abnormal) other biomarkers (NS) continued

364 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-2 Continued Age Range E-Cigarette % Men E-Cigarette Pattern of Use Study % C-Smoker Device and Cotinine Reference Design Population % F-Smoker Characteristics Levels Farsalinos et RCT also Smokers not 44.0 years “Categoria” NR al., 2016 analyzed attempting (mean) e-cigarette as a CO to quit from 63% model Catania, Italy, 100% 401, Arbi followed for 0% Group Srl 52 weeks, (disposable recruited in cartridge and 2010–2011 3.7-V, through a 90mAh smoking lithium ion cessation battery). clinic and E-liquid offered to use nicotine: e-cigarettes - 2.4% 12 weeks - 2.4% 6 weeks + 1.8% 6 weeks - 0% 12 weeks Polosa et al., CO Regular 53.9 years NR Daily use from 2016 smokers on (mean) 10 to 14 months treatment for 56% (83.7% more hypertension 48% (some than 12 months) at an dual users) outpatient 52% clinic in Catania, Italy (period of recruitment NR)

CARDIOVASCULAR DISEASE 365 Comparison Study Groups na Endpoints Results Adjustmentb RCT arms: 63/ SBP (mmHg) RCT: mean (SD) SBP decreased Some analyses - 0% nicotine 66/ DBP (mmHg) from 128 (15) at baseline to 123 adjusted for - 1.8% 61 HR (bpm) (14) mmHg at 52 weeks sex, age, and - 2.4% 93/ at baseline (p = 0.004) with no difference by weight change CO groups: 34/ and at 8 treatment group. - Smokers 18 follow-up CO: adjusted mean change (95% - Dual users visits over 52 CI) in SBP over time compared - Sole users weeks with smokers: (called Dual users: −6.76 (−13.39, −0.13) failures, mmHg reducers, and e-cigarette users: −14.25 (−23.70, quitters in the −4.81) mmHg paper) Stratified analysis by baseline BP:c Elevated (n = 66): mean (SD) change in SBP (mmHg) over time was 6.0 (12.5) (p = 0.002), 10.8 (10.1) (p < 0.001), and 16.3 (11.3) (p = 0.005) for smokers, dual users, and sole users, respectively. Normal (n = 79): No difference by group. No differences over time were observed for HR or for DBP by RCT treatment and CO group overall or stratified by baseline BP (elevated or normal). - Smokers 46/ SBP (mmHg) Median (IQR) Sex, age, - Dual users 23/ DBP (mmHg) 145 (137, 152)/137 (132, 144)/ weight, - Single users 20 HR (bpm) 134 (130, 142) changes in Measured at 87 (85, 90)/83 (80, 92)/81 (74, 84) SBP between baseline, 6 78 (72, 85)/77 (70, 83)/80 (75, 86) pre-baseline and 12 months 145 (136, 150)/130 (121, 140)/ and baseline % HT control 130 (123, 138) <10 mmHg smokers/ 85 (85, 90)/80 (71, 90)/80 (75, 87) e-cigarette 79 (72, 84)/76 (71, 92)/80 (76, 90) users p-value comparing e-cigarette users versus smokers from baseline to 12 months < 0.001 for SBP and DBP and 0.71 for HR 20/37 at 6 months and 22/49 at 12 months continued

366 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-2 Continued NOTES: C-smoker = current smoker; CO = crossover; DBP = diastolic blood pressure; F-smoker = former smoker; HF = high frequency; HR = heart rate; HRV = heart rate vari- ability; HT = hypertension; LF = low frequency; MAP = mean arterial pressure; NR = not reported; NS = not significant; RCT = randomized controlled trial; SBP = systolic blood pressure; XS = cross-sectional. a Final sample size used in the analyses. For Moheimani and colleagues (2017), the sample size was initially larger, but 1 participant among non-users of e-cigarettes was ex- cluded ­ ecause of active smoking, and 2 and 5 e-cigarette users were excluded because of b active smoking or because of e-cigarette use the day of the study, respectively. Also, only 12 ­ -cigarette users had sufficient bio-specimens available to measure biomarkers. For e F ­ arsalinos and colleagues (2016), 300 (100 in each group) were initially recruited for the RCT, but 183 completed the study at 52 weeks (61 percent response rate with no difference by treatment group, so the estimated sample size is 61 participants in each treatment group available for the statistical analysis). b Adjustment for potential confounding through regression modeling, matching, stratifica- tion, or other strategy. c Elevated BP defined as SBP/DBP greater than or equal to 130/85 mmHg. Czogała et al., 2012; Fogt et al., 2016). The two-arm separate comparison groups study (Farsalinos et al., 2014) and the one-arm before/after study (St.Helen et al., 2016) required no smoking or e-cigarette use several hours prior to the interventions. In the 13 short-term clinical studies, outcomes were measured before and after the interventions. These studies contribute to assessing the short-term effect of using an e-cigarette regardless of the comparison group. In the remaining studies, the outcomes were measured cross- sectionally with the assessment of e-cigarette exposure in one study, and over 1 year in two studies. The following study outcomes were measured: • heart rate in 14 studies (Cooke et al., 2015; Czogała et al., 2012; Eissenberg, 2010; Farsalinos et al., 2014, 2016; Fogt et al., 2016; Moheimani et al., 2017; Polosa et al., 2016; Spindle et al., 2017; St.Helen et al., 2016, 2017; Szołtysek-Bołdys et al., 2014; Vansickel et al., 2010; Yan and D’Ruiz, 2015); • blood pressure in 9 studies (Cooke et al., 2015; Czogała et al., 2012; Farsalinos et al., 2014, 2016; Fogt et al., 2016; Moheimani et al., 2017; Polosa et al., 2016; Szołtysek-Bołdys et al., 2014; Yan and D’Ruiz, 2015); • hypertension control in 1 study (Polosa et al., 2016); • biomarkers of oxidative stress in 2 studies (Carnevale et al., 2016; Moheimani et al., 2017); • biomarkers of inflammation in 1 study (Moheimani et al., 2017);

CARDIOVASCULAR DISEASE 367 • endothelial function based on brachial artery flow–mediated dila- tion in 1 study (Carnevale et al., 2016); • arterial stiffness in 1 study (Szołtysek-Bołdys et al., 2014); • endothelial progenitor cells and microvesicles in 1 study (Antoniewicz et al., 2016); • autonomic control and heart rate variability in 2 studies (Cooke et al., 2015; Moheimani et al., 2017); and • cardiac geometry and function in 1 study (Farsalinos et al., 2014). The summary of the main results for these outcomes is presented below. Heart Rate Among the 11 studies that have evaluated short-term changes in heart rate, 10 studies measured heart rate before and after the intervention and 1 study measured heart rate only at the end of the intervention (Fogt et al., 2016). Five studies found higher heart rate levels after versus before e-cigarette use (Cooke et al., 2015; Spindle et al., 2017; St.Helen et al., 2016, 2017; Yan and D’Ruiz, 2015), all of them published between 2015 and 2017, while five studies published between 2010 and 2014 found no difference in heart rate after versus before e-cigarette use (Czogała et al., 2012; Eissenberg, 2010; Farsalinos et al., 2014; Szołtysek-Bołdys et al., 2014; Vansickel et al., 2010). The study by Fogt and colleagues (2016) also found similar heart rate levels after using an e-cigarette with 0 versus 18 mg/ ml nicotine. The studies that found increases in heart rate were charac- terized by using tank-style devices, own devices, and/or confirmed that nicotine or cotinine biomarkers had increases following e-cigarette use. In those studies, the change in heart rate after versus before e-cigarette use ranged from an increase in 1.2 beats per minute (bpm) in a study of a GreenSmartLiving e-cigarette with nicotine 18 mg/ml (Cooke et al., 2015) to 17.2 bpm in a study of a tank-style e-cigarette device with strawberry flavoring with nicotine 18 mg/ml that closely evaluated the maximum change, which occurred at 5 minutes after completing a 15-puff session (St.Helen et al., 2017). Studies that found no changes generally used first- and second-­ eneration e-cigarette devices and had no or small changes in g nicotine-related biomarkers. Studies that compared changes in heart rate levels before and after smoking a combustible tobacco cigarette found marked increases in heart rate, generally larger than those found with e-cigarettes. However, most of the studies comparing e-cigarettes with combustible tobacco cigarettes have been done using first- and second- generation devices that did not markedly increase nicotine or cotinine levels in plasma. In the Yan and D’Ruiz (2015) study comparing a blu

368 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES e-cigarette to a Marlboro cigarette (plasma nicotine levels ranged from 13.7 ng/ml to 22.5 ng/ml plasma nicotine after 1 hour of ad lib e-cigarette use depending on the e-liquid formulation compared with 29.5 ng/ml after 1 hour of ad lib use of Marlboro cigarettes), the change in heart rate after versus before e-cigarette ranged from a mean (SD) of 1.9 (7.4) bpm (p = 0.24) for a blu e-cigarette with classic e-liquid with 1.6 percent nico- tine and 75 percent glycerol to 4.1 (5.7) bpm (p = 0.002) for a blu e-cigarette with menthol e-liquid, 2.4 percent nicotine and 75 percent glycerol, which compared with a change of 4.3 (5.4) bpm (p = 0.001) following a Marlboro cigarette. These results indicate that in some instances the changes in heart rate induced by e-cigarettes are similar to those induced by com- bustible tobacco cigarettes. Short-term effects of e-cigarette use on heart rate do not necessar- ily mean that chronic e-cigarette use increases resting heart rate, which is an established predictor of poor clinical cardiovascular health. In a cross-­ ectional study of daily e-cigarette users from Los Angeles, resting s heart rate was similar among e-cigarette users compared with non-users (Moheimani et al., 2017) (see Table 9-2). An important limitation of this study is the lack of adjustment for sociodemographic characteristics and cardio­ ascular disease risk factors between e-cigarette users and non- v users. Resting heart rate was also similar over a 52-week period compar- ing e-cigarettes “Categoria model 401” with different levels of nicotine (0 percent, 2.4 percent + 1.8 percent, and 2.4 percent) randomly assigned to smokers in a cessation clinic (Farsalinos et al., 2016), as well as in a group of hypertensives using e-cigarettes as single or dual use compared with smoking. Synthesis Recent intervention studies using tank-style devices and devices owned by e-cigarette users and with confirmation of nicotine intake have consistently found increases in heart rate shortly after e-cigarette use. Ear- lier studies, using first- and second-generation devices, found no changes in heart rate following e-cigarette use. However, those studies were char- acterized by small or no increase in nicotine or cotinine biomarker levels. The crossover design, including randomization of the intervention order in several studies, is an ideal experimental design to evaluate short-term effects minimizing interindividual sources of variability in heart rate. The effect estimates, although generally smaller than those observed for tobacco cigarettes, get closer in value for some types of e-cigarettes, gen- erally related to higher nicotine intake. It is well known that nicotine increases heart rate, which provides biological plausibility to these find- ings. For studies evaluating the association between e-cigarette use and

CARDIOVASCULAR DISEASE 369 heart rate over longer-term periods, the three studies available found no association, although the studies did not adjust for sociodemographic variables and the type of e-cigarettes was not well characterized. Blood Pressure A total of six clinical studies measured short-term changes in SBP/ DBP following e-cigarette use, five of them including measures before and after the experiments (Cooke et al., 2015; Czogała et al., 2012; Farsalinos et al., 2014; Szołtysek-Bołdys et al., 2014; Yan and D’Ruiz, 2015). All the studies indicated that they had recruited healthy participants without hypertension. Some studies had confirmed that SBP/DBP were less than or equal to 140/90 mmHg or even lower. In a crossover study assessing GreenSmartLiving e-cigarettes (Cooke et al., 2015), the mean (SD) change in SBP before and 10 minutes after the intervention was approximately −2.0 (3.0) and 2.0 (3.0) mmHg for 0 and 18 mg/ml nicotine concentrations, respectively, and the differences between those two groups were signifi- cant (p ≤ 0.03). The corresponding changes for DBP were −2.0 (3.0) and 4.0 (6.0) mmHg (p = 0.001). SBP and DBP in that experiment were also higher with nicotine compared with no nicotine during supine, tilt, and recovery experiments in addition to the rest measures. In the cross-over trial using blu e-cigarettes with five different e-liquids (Yan and D’Ruiz, 2015), the increase in mean (SD) SBP measured before and after the inter- vention (which included an ad lib period) ranged from 1.1 (11.1) mmHg (p = 0.63) for Classic Tobacco with 2.4 percent nicotine and 75 percent glycerol to 5.8 (10.0) mmHg (p = 0.02) for Classic Tobacco with 1.6 percent nicotine and 75 percent glycerol. The corresponding increase after smok- ing a Marlboro cigarette was 5.7 (12.4) mmHg (p ≤ 0.04). The correspond- ing changes for DBP ranged from 3.2 (7.3) mmHg (p = 0.05) for blu with menthol and 2.4 percent nicotine and 75 percent glycerol to 6.8 mmHg for three other types of blu cigarettes with different compositions (p < 0.001). The increase in DBP for a Marlboro cigarette was also 6.8 (7.1) mmHg (p < 0.001). Consistent with these findings, in the study by Farsalinos and colleagues (2014), DBP increased both after exposure to a cigarette (mean change [SD] = 4.4 [3.3], p < 0.001) and to an e-cigarette (3.0 [3.6], p < 0.001), while SBP increased after a cigarette (6.6 [5.2], p < 0.001) but not after an e-cigarette (0.7 [4.6], p = 0.37). In the study that compared blood pressure levels before and 10 minutes after a personal cigarette or an e-cigarette (Ego-3) in female students from Silesia, Poland (Szołtysek-Bołdys et al., 2014), the investigators reported small, statistically insignificant increases in SBP and DBP after both e-cigarettes and cigarettes, but the numbers are not shown. In another study in Poland, a first-generation e-cigarette was not associated with short-term changes in SBP/DBP, while a combustible

370 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES tobacco cigarette was associated with increases in DBP. In the study that reported blood pressure levels only at the end of the experiments (and thus does not allow assessment of the effect of using the e-cigarette com- pared with baseline) (Fogt et al., 2016), mean (SD) SBP was lower for the e ­ -cigarette with 18 versus 0 mg/ml, 112.1 (6.8) versus 115.8 (8.0), p = 0.04, while mean (SD) DBP was higher at 76.6 (6.0) versus 73.6 (8.3), p = 0.04. During the exercise test, peak SBP was similar for both levels of nicotine, while peak DBP was higher for those with nicotine. Short-term effects of e-cigarette use on SBP/DBP do not necessarily mean that chronic e-cigarette use increases resting blood pressure levels. In a cross-sectional study of daily e-cigarette users from Los Angeles, mean SBP was borderline significantly higher in e-cigarette users versus non-users (115.8 versus 109.0 mmHg, p = 0.07), while DBP was similar (Moheimani et al., 2017) (see Table 9-2), although the study did not adjust for sociodemographic characteristics and cardiovascular disease risk fac- tors between e-cigarette users and non-users. In the studies from Catania, Italy, SBP and DBP decreased over time in participants who switched from tobacco cigarettes to e-cigarettes, especially those who achieved sole use (Farsalinos et al., 2016; Polosa et al., 2016). In the group of hyper- tensives, there was an improvement in hypertension control at 6 months and 12 months (Polosa et al., 2016). The study without hypertensives is limited by • a relatively large loss of study participants during follow-up; • lack of detailed reporting for the initial study design based on three treatment groups; and • the observational design comparing sole and dual e-cigarette user to smokers in the secondary analyses, although the three groups were comparable at baseline by sex, age, pack-years, and blood pressure levels. The study among hypertensives is limited by • small sample size; • unclear description of how many participants with hypertension were available initially and if they were selected using a random sampling strategy; • lack of details on the e-cigarette devices and the e-liquid used by the participants; and • the retrospective data collection based on clinical records. The study matched for age, sex, and lack of fluctuation in SBP com- paring a pre-baseline visit occurring 6–13 months prior with the baseline

CARDIOVASCULAR DISEASE 371 visit. It is unclear how the authors ensured recruitment of participants who have not had changes in their blood pressure levels of more than 10 mmHg for 6–12 months, but studied the change in the following year. It is possible that the study has been done completely retrospectively. Synthesis Overall, for SBP, there are some inconsistent findings, with the major- ity of studies finding weak positive increases or no changes with the use of e-cigarettes, while experiments with combustible tobacco cigarettes found consistent increases. From studies with different levels of nicotine, it seems that lower nicotine concentrations resulted in weaker increases in SBP or even lower SBP levels than no nicotine. For DBP, on the other hand, the studies consistently show short-term increases in DBP follow- ing the use of an e-cigarette that delivers nicotine with a magnitude of the effect similar to the increase observed when smoking a cigarette. The crossover design, including randomization of the intervention order in several studies, is an ideal experimental design to evaluate short-term ­ effects minimizing interindividual sources of variability in SBP/DBP. These findings are consistent with other studies in humans supporting short-term effects of e-cigarette use on markers of endothelial function and arterial stiffness (see below). The short-term effect of nicotine from e-cigarettes on SBP and DBP is consistent with findings from other nico- tine delivery products including tobacco cigarettes and even nicotine replacement products. Regarding chronic health effects on blood pressure levels, the evidence is very limited as there is only one study comparing e-cigarette use to non-use, and two studies comparing e-cigarette use to smoking, one including patients with hypertension. Oxidative Stress, Inflammation, Endothelial Function, and Arterial Stiffness (Arteriosclerosis) Two studies have measured biomarkers of oxidative stress, one evalu- ating short-term changes in a study of 20 current smokers and 20 never smokers exposed to a cigarette or an e-cigarette in a non-randomized c ­ rossover design (all participants exposed first to the cigarette and 1 week later to the e-cigarette) (Carnevale et al., 2016), and the other a cross- sectional study of e-cigarette users compared with non-users from Los Angeles (Moheimani et al., 2017). In the crossover study, the following biomarkers of oxidative stress were measured in serum before and 30 minutes after exposure to a cigarette or an e-cigarette: soluble NOX2- derived peptide (sNOX2-dp), a marker of nicotinamide adenine dinu- cleotide phosphate (reduced form) oxidase activation, nitric oxide bio-

372 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES availability, a signaling molecule with a major role in the regulation of vasodilation and endothelial function, and 8-iso-prostaglandin F2α (8-iso- PGF2α). The study reported the mean (SD) before and after the cigarettes and the e-cigarettes. The mean change in serum before and after cigarette and e-cigarette exposure was 14.6 (p < 0.001) and 8.6 (p < 0.001) pg/ml for sNOX2-dp, 68 (p < 0.001) and 54 (p < 0.001) pmol/L for 8-iso-PGF2α, −15.8 (p < 0.001) and −9.6 (p < 0.001) µM for NO bioavailability, and −1.5 (p < 0.001) and −1.0 (p < 0.001) µmol/mmol for vitamin E, respectively. Although the magnitude of the effect was weaker compared with the changes induced by a combustible tobacco cigarette, these experiments suggest that e-cigarettes can also increase levels of oxidative stress and reduce the levels of antioxidants. A major limitation of this study is the lack of information on the type of e-cigarette device and e-liquid used. Additional research would be needed to confirm these short-term effects and for which types of devices, as well as to evaluate the long-term effects of e-cigarette use on biomarkers of oxidative stress. These findings are consistent with in vitro and in vivo studies that are discussed in more detail in Chapter 7. In summary, several studies in vitro have shown that human vascular endothelial cells show increased reactive oxygen species with e-cigarette extract compared with controls (Anderson et al., 2016). Mice exposed to e-cigarette aerosol for several weeks showed increased levels of oxidative stress, macrophage-mediated inflammation, and inflammatory cytokines including interleukin-6 (Lerner et al., 2015). In the cross-sectional study from Los Angeles (see Table 9-2), oxi- dized LDL was higher in e-cigarette users versus non-users, while there were no differences in other biomarkers of oxidative stress or inflam- mation, although the sample size was small (Moheimani et al., 2017). The same crossover study that measured oxidative stress biomarkers also assessed endothelial function by measuring flow-mediated dilation (FMD) (Carnevale et al., 2016), a marker of vascular reactivity in large arteries that measures the change in arterial diameter following reactive hyperemia. FMD was measured based on ultrasound assessment of basal brachial diameter and endothelial-dependent FMD of the brachial artery following established guidelines. FMD is expressed as a change in post- stimulus diameter evaluated as a percentage of the baseline diameter, with a lower percentage reflecting worse endothelial function. Mean (SD) brachial artery FMD changed from 6.7 (4.3) percent to 3.4 (3.9) percent (p < 0.001) and from 6.7 (3.6) percent to 4.3 (2.2) percent (p = 0.001) before and after, respectively, a cigarette and an e-cigarette. Although the change was larger after a cigarette (−3.3 percent change) than an e-cigarette (−2.4 percent change), both were statistically significant. The study did not provide detailed information on changes in pulse-wave velocity. The

CARDIOVASCULAR DISEASE 373 implications of these findings for long-term endothelial function in long- term e-cigarette users need to be evaluated. The short-term effect of e-cigarettes on endothelial function has also been evaluated based on changes in endothelial progenitor cells (EPCs) measured with flow cytometry and reported as EPC events (Antoniewicz et al., 2016). EPCs are stem cells mainly derived from the bone marrow that have been proposed as a biomarker of endothelial function as they play a critical role in the maintenance, differentiation, and regeneration of endothelial cells following vascular injury or neogenesis (Lekakis et al., 2011). In experiments comparing EPC levels before and 1 hour, 4 hours, and 24 hours after exposure to an eGoXL e-cigarette with nicotine 12 mg/ml and 49.4 percent/44.4 percent PG/glycerol without flavors, EPC events increased at 1 hour and 4 hours and returned to normal at 24 hours (see Figure 9-2). No changes were observed for control periods conducted with 1-week washout in a randomized crossover manner and in the same conditions as the e-cigarette experiment. These short-term effects of e-cigarettes on EPCs could be related to nicotine, as nicotine has been shown to increase short-term increases of EPCs. In addition to EPCs, the same experiment also measured microvesicles (MVs) from the cell mem- brane. The MVs consist of a lipid bilayer that can be released from all cell types in the circulation, such as leukocytes, erythrocytes, endothelial cells, and platelets. No differences were found in MVs overall, by cell origin (endothelial, platelet, or leukocyte) or by markers of inflammation (high-mobility group protein B1 [HMGB1], P-selectin, CD40 ligand), but a statistically significant difference was found for endothelial MVs with E-selectin (CD144 + CD62E), with higher levels at 4 hours after the experi- ment (median = 28 [IQR = 17, 65] versus 23 [14, 42]) that returned to nor- mal at 24 hours (20 [15, 40] versus 23 [11, 37]), p = 0.038.1 More research is needed to understand the short-term effects of e-cigarettes on endothelial function and the long-term implications of these findings. Indeed, a short- term increase in EPCs does not necessarily translate to acute endothelial injury. In epidemiological studies, lower rather than higher EPC levels are associated with higher risk of coronary heart disease. The use of novel, relatively easy-to-obtain biomarkers such as EPCs and MVs could be use- ful to assess both the short-term and the long-term effects of e-cigarettes on cardiovascular disease. Arterial elasticity is essential for blood flow. The hardening or stiffen- ing of the arteries, which is also called arteriosclerosis, plays an impor- tant role in the development of cardiovascular disease. The term arterial 1Chapter 7 also includes this study in its review and presents effects of e-cigarette expo- sure on overall MVs. The committee finds no conflict between the evidence presented in this chapter and the evidence presented in Chapter 7.

374 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES stiffness is commonly used when arteriosclerosis is measured based on the pulse wave graph using photoplethysmography. One study has mea- sured arterial stiffness at the height of the phalanges artery before and 10 minutes after a personal cigarette or an e-cigarette (Ego-3) exposure in female students from Silesia, Poland (Szołtysek-Bołdys et al., 2014). The main study outcomes are the stiffness index (SI) measured in meters per second and the reflection index (RI) measured in percentage. SI is the ratio of the patient height in meters and the time between peaks of the systolic and diastolic components in the pulse wave graph. The RI is the ratio of diastolic and systolic component heights, expressed as percentage. In those experiments, in which SI and RI were measured before and 10 min- utes after smoking a cigarette, and 1 week later after using an e-cigarette (Ego-3) with nicotine 24 mg/ml, SI was reduced from 6.75 to 6.56 (p = 0.006) after the cigarette but remained similar (6.73 and 6.75, changes not statistically significant) after an e-cigarette. RI was reduced (54.0 to 49.6 percent, p = 0.01) after a cigarette. The reduction after an e-cigarette (52.0 percent to 50.8 percent) was not statistically significant, although the exact p-value was not reported. The findings of this experiment would indicate that e-cigarettes would not induce short-term changes in arterial stiffness, contrary to combustible tobacco cigarettes. Given the findings FIGURE 9-2 Endothelial progenitor cells (EPCs) during e-cigarette inhalation and control. NOTES: Two-way, multiple measures ANOVA were significant for the interaction of exposure and time (p = 0.002). Separate time-point analysis was significant for 1 hour versus baseline, *p = 0.003; and 4 hours versus baseline, †p = 0.036. SOURCE: Antoniewicz et al., 2016.

CARDIOVASCULAR DISEASE 375 for DBP as well as some of the findings reported for endothelial dysfunc- tion, it is important to further evaluate the short- and long-term effects of e-cigarette smoking on arterial stiffness in larger studies. Synthesis Although the number of studies evaluating the effects of e-cigarettes on measures of oxidative stress, endothelial dysfunction, and arterial stiff- ness is small, these outcomes are interrelated and are considered in the underlying pathophysiological pathway toward clinical cardiovascular disease, including coronary heart disease, stroke, and peripheral artery disease. A major limitation is that these outcomes were evaluated short term rather than long term and it is unknown if these short-term findings have long-term consequences for the cardiovascular system. Research further evaluating these subclinical measures of cardiovascular disease is needed. Cardiac Geometry and Function The two-arm intervention study comparing the short-term effects of combustible tobacco cigarettes in smokers and e-cigarettes in e-cigarette users conducted measures of echocardiography before and 5 minutes after smoking a cigarette or using an e-cigarette (Farsalinos et al., 2014). During the echocardiography measures of flow diastolic velocities (E, A), their ratio (E/A), deceleration time (DT), isovolumetric time (IVRT), and corrected-to-heart rate IVRT (IVRTc) were measured. Mitral annulus sys- tolic (Sm) and diastolic (Em, Am) velocities were estimated. Myocardial performance index was calculated from Doppler flow (MPI) and tissue Doppler (MPlt). Longitudinal deformation measurements of global strain (GS), systolic (SRs) and diastolic (SRe, SRa) strain rate were also per- formed. While the study focused its presentation of the findings compar- ing the effects of smoking a cigarette in smokers to vaping an e-cigarette among e-cigarette users, the comparability of those two groups is unclear. A better study design would be to evaluate the changes that occur before and after within each group. For e-cigarette users, none of the changes in the echocardiograph measures were statistically significant. However, some were borderline. For example, there was a mean (SD) change of 1.6 (5.6) cm/second in A flow diastolic velocity (p = 0.08), which was in the same direction as that observed for combustible tobacco cigarette s ­ mokers. The change in Em of 0.2 (0.7) cm/second MPIt (−0.01 [0.04], p = 0.08) was in the opposite direction from that among smokers. For GS the change (SD) was −0.4 (1.2) and almost statistically significant (p = 0.06), although also in the opposite direction from that among smokers. Overall,

376 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES the implications of this study are unclear. First, because the study is not using a crossover design, the interventions were not randomized, and the comparability of smokers and e-cigarette users is unclear. Second, the usefulness of echocardiographic measures to assess short-term changes is unclear. Cardiac function and echocardiographic measures can be difficult to obtain and it is unclear if changes in those measures can be observed so quickly. These measures, moreover, are user dependent and if the examiner is aware of the intervention and the before and after status of the participant, the results may be influenced. Finally, this study used an early-generation e-cigarette device, so the relevance for currently used e-cigarettes is also unknown. Autonomic Control One study measured short-term effects of e-cigarette use on auto- nomic cardiovascular control under conditions of orthostatic stress (Cooke et al., 2015). No differences were observed by treatment group. In the cross-sectional study of e-cigarette users from Los Angeles com- pared with non-users, heart rate variability was measured with an echo- cardiogram (ECG) obtained during 5 minutes of quiet rest and during 5 minutes of controlled breathing at 12 breaths per minute (stimulus for the vagal tone). Three main spectral components were distinguished: high frequency (HF = 0.15–0.4 Hz, indicator of vagal activity), low frequency (LF = 0.04–0.15 Hz, a mixture of both vagal and sympathetic activity), and the ratio of LF to HF, reflecting cardiac sympathetic balance. Time-domain analysis was not applied because the ECG recording was too short. In a second study, Moheimani and colleagues (2017) found the HF component decreased significantly in e-cigarette users compared with non-users (mean 46.5 versus 57.8, p = 0.04) while the LF and the LF/HF ratio increased significantly (52.7 versus 39.9, p = 0.03 and 1.37 versus 0.85, p = 0.05). No differences were observed between e-cigarette users and non-users in the changes of HF, LF, and LF/HF ratio during the con- trolled breathing maneuver. Study limitations include the small sample size, unclear description of the sources and forms of recruitment and response rate, the lack of adjustment or matching for sociodemographic and lifestyle risk factors (in particular given the imbalance by sex, former smoking status, and pack-years), and the lack of details on the e-cigarette devices and the e-liquid used by the participant. Outcome assessment was conducted using high-quality protocols and is described in detail.

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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