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Public Health Consequences of E-Cigarettes (2018)

Chapter: 9 Cardiovascular Disease

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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

9 Cardiovascular Disease Active smoking of combustible tobacco cigarettes and exposure to secondhand tobacco smoke are established causes of clinical cardiovascular disease. Prior Surgeon General Reports concluded that the evidence is sufficient to infer that active 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 epidemiologic 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 of 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 cigarette smoke, secondhand tobacco smoke, and ambient air pollution showed that the exposure–response relationship between fine particulate matter and cardiovascular disease mortality is relatively steep at low levels of exposure and it plateaus at higher levels. Because the particle characteristics and composition 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 included 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, in particular the heating coil, is a source of metals (see Chapter 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 contractility (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 have minimized potential effects on cardiovascular disease (Benowitz and Fraiman, 2017), others see greater risk (Bhatnagar, 2016). Possible mechanistic pathways for particulates, metals, and other toxic chemicals, which are also found in e-cigarette aerosols and 9-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

9-2 PUBLI HEALTH CONSEQU IC H UENCES OF E-CIGARET TTES could thu be by whi exposure to e-cigaret influence cardiovas us ich e ttes es scular diseas related to se atheroscllerosis and coronary hea disease, ar summariz in Figure 9-1. This fi art re zed e figure is insp pired from the well-establi ished eviden of the tox nce xicity of commbustible tobbacco produc on the cts cardiovas scular system as summa m, arized in the Surgeon Ge eneral Repor (2014). A major differ rt rence among th potentially cardiotoxic substances that are fou in combu he y c s und ustible tobac cigarette cco es, but not in e-cigarettes, is the lack of combust n k tion chemica such as p als polycyclic ar romatic hydrocar rbons and car rbon monox (see Cha xide apter 5). The possibility that e-cigare e ettes may increase the risk of cardiovascula disease mu be evalu ar ust uated carefull given the high burden of ly n cardiovas scular diseas worldwide and the im se mportance of the burden o disease in the estimat f of n tion of attribu utable risk. CH HARACTE ERIZATION OF DISEA ENDP OINTS AN INTERM N ASE ND MEDIATE OUUTCOMES Relativel few studie have inves ly es stigated the cardiovascu effects of e-cigarette products. In ular e n particular there are no epidemiol r, n logic studies evaluating clinical outc s comes such as coronary heart herosclerotic peripheral artery diseas or establi disease, stroke, or ath s c se, ished subclin nical outcommes of underllying atherossclerosis suc as carotid intima medi thickness or coronary artery ch ia y calcificat tion. Clinica outcomes such as coro al s onary heart ddisease (inclu uding myoca ardial infarct tion and sudd cardiac death), stroke and periph den d e, heral artery ddisease have been the co e ornerstone of f prospecti epidemio ive ologic studie evaluating the vascula effects of combustible tobacco es g ar e cigarettes Subclinica measures of atheroscle s. al erosis, such as carotid in ntima media thickness or r coronary artery calcification, are also conside y ered excellen measures of cardiova nt ascular risk th hat FIGURE 9-1 Conceptual framewor of plausible pathways, i rk e including mecchanisms and intermediary d y outcomes, by which ex xposure to e-c cigarettes influ uences cardio ovascular dise ease. SOURCE Adapted fro HHS, 2014. E: om PR REPUBLICA ATION COP UNCO PY: ORRECTED PROOFS D

CARDIOVASCULAR DISEASE 9-3 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 cardiovascular outcomes. None of the studies on e- cigarettes and cardiovascular disease conducted so far and summarized below, however, have measured 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 (coronary heart disease, stroke and peripheral artery disease) and subclinical 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 and other alterations in myocardial cells and human vascular cells of e-cigarette aerosols; studies conducted in vivo, evaluating relevant mechanistic pathways for cardiovascular toxicity in mice; and clinical experiments, generally cross-over 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 combustible tobacco cigarettes and to no smoking. A few studies have evaluated the associations between e-cigarette use and heart rate, heart rate variability, 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 evaluating 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 comparing 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 powerful 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 brachial blood pressure is one of the best established contributors of clinical cardiovascular disease and mortality, including myocardial infarction, stroke, and renal failure when not detected early and treated appropriately (James et al., 2014). Hypertension diagnosis, treatment, and control are critical for cardiovascular disease prevention and control. Hypertension can be defined when either systolic or diastolic blood pressure are elevated. While there are blood pressure cut-offs 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, resulting in short-term elevations that could be related to the effects of nicotine. 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 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

9-4 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES pressure wave along the arterial 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). 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 individuals, without established cardiovascular disease or major cardiovascular risk factors, endothelial function is also related to increased arterial stiffness. Because endothelial function is an early marker of atherosclerosis (narrowing of the arteries because of the presence of plaque) and clinical cardiovascular disease characterized by a reduced bioavailability of endothelium-derived nitric oxide (NO), it shows the close interrelatedness 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 cardiovascular 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. HUMAN EVIDENCE FROM 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 minutes to hours following the intervention (see Table 9-1). Among them, 11 were cross-over studies in which all participants received 2 or more interventions (in 6 of them the order of the intervention 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; Czogala et al., 2014; Eissenberg, 2010; Spindle et al., 2017; Szo tysek-Bo dys 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). The literature search also identified 3 studies evaluating cardiovascular-related outcomes over a longer period than the 13 acute clinical studies (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 (called reducers), and smokers (called failures) according to their continuation of combustible tobacco smoke (n = 145 for participants with continuous e-cigarette/smoking status over time) (Farsalinos et al., 2016); and a PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-5 cohort of hypertensive patients who were e-cigarette users compared 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 participants across the 15 studies (356 in the short-term clinical studies and 306 in the epidemiologic studies). Study participants were recruited from Catania (Italy), Khallithea (Greece), Los Angeles (California), Lincoln (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 studies), and included a balanced number of men and women, except in one study restricted to women (Szo tysek-Bo dys et al., 2014) and another study that included 90 percent men (Farsalinos et al., 2014). Mean age of the participants in the epidemiologic studies ranged from 33 to 54 years, and in one study all participants had hypertension at baseline. In a total of seven studies, all participants were current smokers (Antoniewicz et al., 2016; Czogala et al., 2014; Eissenberg, 2010; Farsalinos et al., 2016; Szo tysek-Bo dys 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 participants were naïve e- cigarette users (Antoniewicz et al., 2016; Cooke et al., 2015; Czogala 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; Szo tysek-Bo dys et al., 2014); and in one study whether participants were naïve e-cigarette users was not reported (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 in three studies (different eGO models) (Antoniewicz et al., 2016; Farsalinos et al., 2014; Szo tysek-Bo dys et al., 2014); cigalikes in five studies (Green Smart living in two studies) (Cooke et al., 2015; Fogt et al., 2016); blu in one study (Yan and D’Ruiz, 2015); Mild in one study (Czogala et al., 2012); NJOY NPRO and Hydro in two studies (Eissenberg, 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 cotinine biomarkers were reported in 10 studies and 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 (Moheimani et al., 2017; Spindle et al., 2017; St.Helen et al., 2017; St.Helen et al., 2016). Few studies provided details on actual wattage and resistance (Antoniewicz et al., 2016; Farsalinos et al., 2014; St.Helen et al., 2017; Szo tysek-Bo dys et al., 2014) and no studies provided 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 (Szo tysek-Bo dys et al., 2014), although some studies reported the total amount of nicotine in the cartridge, but not the actual concentration PREPUBLICATION COPY: UNCORRECTED PROOFS

9-6 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES (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 studies actually reported the concentrations of other constituents beyond nicotine (Antoniewicz et al., 2016; Farsalinos et al., 2014). Regarding flavors, only one study used a vanillin flavor (Farsalinos et al., 2014), 2 studies mentioned menthol, one allowing the choice of a menthol flavoring (Eissenberg, 2010), another study specifically tested menthol (Yan and D’Ruiz, 2015), and one study compared strawberry flavor, tobacco flavor, 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; Czogala et al., 2012; Eissenberg, 2010; Farsalinos et al., 2014; Szo tysek-Bo dys 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; and one study compared the same e-cigarette and e-liquid with and without a mouthpiece (Spindle et al., 2017). The washout periods ranged from less than 24 hours (St.Helen et al., 2017) to 1 week in cross-over studies (Antoniewicz et al., 2016; Carnevale et al., 2016; Cooke et al., 2015; Czogala et al., 2012; Fogt et al., 2016). The two-arm separate comparison groups study and the one-arm before/after study required no smoking or e-cigarette use several hours prior to the interventions (Farsalinos et al., 2014; St.Helen et al., 2016). 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; Czogala 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; Szo tysek-Bo dys et al., 2014; Vansickel et al., 2010; Yan and D’Ruiz, 2015); • blood pressure in 9 studies (Cooke et al., 2015; Czogala et al., 2012; Farsalinos et al., 2014; Fogt et al., 2016; Moheimani et al., 2017; Szo tysek-Bo dys et al., 2014; Vansickel et al., 2010; 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); • endothelial function based on brachial artery flow mediated dilation in 1 study (Carnevale et al., 2016); • arterial stiffness in 1 study (Szo tysek-Bo dys 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). PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-7 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 (HR), 10 studies measured HR before and after the intervention and 1 study measured HR only at the end of the intervention (Fogt et al., 2016). Give studies found higher HR 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 HR after versus before e-cigarette use (Czogala et al., 2012; Eissenberg, 2010; Farsalinos et al., 2014; Szo tysek-Bo dys et al., 2014; Vansickel et al., 2010). The study by Fogt and colleagues (2016) also found similar HR levels after using an e-cigarette with 0 versus 18 mg/ml nicotine. The studies that found increases in HR were characterized 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 HR after versus before e-cigarette use ranged from an increase in 1.2 beats per minute (bpm) (Cooke et al., 2015) in a study of a Green Smart Living e-cigarette with nicotine 18 mg/ml 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 generation e-cigarette devices and had no or small changes in nicotine-related biomarkers. Studies that compared changes in HR levels before and after smoking a combustible tobacco cigarette found marked increases in HR, 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 study comparing a blu 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 HR 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 nicotine 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 HR induced by e-cigarettes are similar to those induced by combustible tobacco cigarettes. Short-term effects of e-cigarette use on heart rate do not necessarily mean that chronic e- cigarette use increases resting HR, which is an established predictor of poor clinical cardiovascular health. In a cross-sectional study of daily e-cigarette users from Los Angeles, resting heart rate was similar among e-cigarette users compared with non-users (see Table 9-2) (Moheimani et al., 2017). An important limitation of this study is the lack of adjustment for sociodemographic characteristics and cardiovascular disease (CVD) risk factors between e- cigarette users and non-users. Resting heart rate was also similar over a 52-week period comparing 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. PREPUBLICATION COPY: UNCORRECTED PROOFS

9-8 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES 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. Earlier studies, using first and second generation devices, found no changes in heart rate following e-cigarette use. However, those studies were characterized by small or no increase in nicotine or cotinine biomarker levels. The cross-over 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, generally related to higher nicotine intake. It is well known that nicotine increases heart rate, what provides biological plausibility to these findings. For studies evaluating the association between e-cigarette use and 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 were not well characterized. Blood Pressure A total of six clinical studies measured short-term changes in systolic and diastolic blood pressure (SBP/DBP) following e-cigarette use, five of them including measures before and after the experiments (Cooke et al., 2015; Czogala et al., 2012; Farsalinos et al., 2014; Szo tysek- Bo dys 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 cross-over study assessing Green Smart 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 significant (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 intervention (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 of 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 smoking a Marlboro cigarette was 5.7 (12.4) mmHg (p 0.04). The corresponding 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 vegetable glycerol to 6.8 mmHg for three other types of blu cigarettes with different compositions (see A, B and D in the table below) (p < 0.001). The increase in DBP for a Marlboro cigarette was also of 6.8 (7.1) mmHg (p < 0.001). Consistent with these findings, in the study by (Farsalinos et al., 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 (Szo tysek-Bo dys et al., 2014), the investigators reported small, statistically insignificant increases in SBP and DBP both after e-cigarettes and cigarettes, but the numbers are not shown and the figure is difficult to see. In another study in Poland, a first generation e- PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-9 cigarette was not associated with short-term changes in SBP/DBP, while a combustible tobacco cigarette was associated with increases in DBP. Among the study that reported blood pressure levels only at the end of the experiments (and thus does not allow to assess the effect of using the e-cigarette compared 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, 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 (see Table 9-2) (Moheimani et al., 2017), although the study did not adjust for sociodemographic characteristics and CVD risk factors 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 hypertensives, 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; • 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 sample 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 comparing a pre-baseline visit occurring 6 to 13 months prior with the baseline visit. It is unclear how the authors ensured recruitment of participants who have not had changes in their blood pressure levels for 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 majority 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

9-10 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES consistently show short-term increases in DBP following 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 cross-over design, including randomization of the intervention order in several studies, is an ideal experimental design to evaluate short-term effects minimizing inter-individual 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 nicotine 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 evaluating 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 cross-over design (all participants exposed first to the cigarette and one 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 cross-over 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 dinucleotide phosphate (reduced form) oxidase activation, nitric oxide bioavailability, a signaling molecule with a major role in the regulation of vasodilation and endothelial function, and 8-Iso-Prostaglandin F2 (8-iso-PGF2 ). 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, respectively, for sNOX2-dp, 68 (p < 0.001) and 54 (p < 0.001) pmol/L for 8- iso iso-PGF2 , 15.8 (p < 0.001) and 9.6 (p < 0.001) M for NO bioavailability, 1.5 (p < 0.001) and 1.0 (p < 0.001) mol/mmol for vitamin E. 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 control (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), oxidized LDL was higher in e-cigarette users versus non-users, while there were no differences in other biomarkers of oxidative stress or inflammation, although the sample size was small (Moheimani et al., 2017). The same cross-over 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-11 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 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 PG/glycerol 49.4 percent/44.4 percent 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 cross-over 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 shown to increase short-term increases on EPCs. In addition to EPCs, the same experiment also measured microvesicles (MVs) from the cell membrane. 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 leukocytes) 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 experiment (median 28 [IQR 17, 65] versus 23 [14, 42]) that returned to normal 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-cigarette in 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 epidemiologic 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 useful to assess both the short-term and the long-term effects of e-cigarettes on cardiovascular disease. 1 Chapter 7 also included this study in its review and presents effects of e-cigarette exposure on overall MVs. The committee finds no conflict between the evidence presented in this chapter and the evidence presented in Chapter 7. PREPUBLICATION COPY: UNCORRECTED PROOFS

9-12 PUBLI HEALTH CONSEQU IC H UENCES OF E-CIGARET TTES FIGURE 9-2 Endothe elial progenito cells (EPCs) during e-ci or igarette inhalation and con ntrol. NOTE: Tw wo-way, mul ltiple measure ANOVA were significan for the inte es w nt eraction of ex xposure and time (p = 0.002). Separate timeepoint analysi was signifi is icant for 1 hou versus baseline: *p = 0. ur .003 and 4 ho ours versus bas seline: †p = 0.036. 0 SOURCE Antoniewic et al., 2016. E: cz Arterial elasti A icity is essen ntial for bloo flow. The hardening o stiffening of the arteri od e or ies, which is also called arteriosclerosis, plays an important r a n role in the deevelopment of cardiovas scular disease. The term art T terial stiffnes is commonly used wh arteriosclerosis of the arteries is ss hen e measured based on th pulse wav graph usin photoplet d he ve ng thysmograph One stud has measu hy. dy ured arterial sttiffness at th height of the phalange artery befo and 10 m he t es fore minutes after a personal r cigarette or an e-ciga arette (Ego-3 exposure in female stu 3) i udents from Silesia, Pola (Szo tysek- and Bo dys et al., 2014). The main st tudy outcomes are the sti iffness index (SI) measu x ured in m/s a and the reflecction index (RI) measure in percent ( ed tage. SI is th ratio of th patient hei he he ight in meter rs and the ti between peaks of th systolic an diastolic c ime n he nd components in the pulse wave graph e h. The RI is the ratio of diastolic an systolic co s f nd omponents h heights, expr ressed as per rcentage. In those exp periments, in which SI an RI were measured be n nd m efore and 10 minutes after smoking a cigarette, and one we later afte using an e-cigarette (E , eek er Ego-3) with n nicotine 24 mmg/ml, SI wwas reduced from 6.75 to 6.56 (p = 0.006) after th cigarette but remained similar (6. and 6.75, f o he .73 changes not statistica significa after an e-cigarette. RI was redu n ally ant) uced (54.0 to 49.6 percen p o nt, = 0.01) after a cigare The redu a ette. uction after an e-cigarett (52.0 perc to 50.8 p a te cent percent) was not s statistically significan although the exact p- nt, -value was n reported. The finding of this not gs experime would indicate that e-cigarettes would not in duce short-t ent e w term changes in arterial s stiffness, contrary to combustible tobacco cig , e garettes. Giv the findin for DBP as well as s ven ngs P some of the fin ndings report for endot ted thelial dysfu unction, it is important to further eva o aluate the shoort- and long- -term effects of e-cigare smoking on arterial s s ette stiffness in la arger studiess. Synthesis s Although the number of studies evalu A s uating the ef ffects of e-cig garettes on m measures of oxidative stress, endo e othelial dysf function, and arterial stif d ffness is sma these out all, tcomes are interrelat and are considered in the underly ted c n ying pathoph hysiological pathway tow ward clinical PR REPUBLICA ATION COP UNCO PY: ORRECTED PROOFS D

CARDIOVASCULAR DISEASE 9-13 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 2-arm intervention study comparing the short-term effects of cigarettes in smokers and e-cigarettes in e-cigarette users, conducted measures of echocardiography before and after 5 minutes 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 systolic (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 performed. While the study focused their presentation of the findings comparing 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 border line. For example, there was a mean (SD) change of 1.6 (5.6) cm/s in A flow diastolic velocity (p = 0.08), which was in the same direction as that observed for combustible tobacco cigarette smokers. The change in Em of 0.2 (0.7) cm/s MPIt ( 0.01 (0.04) (p = 0.08)) was in the opposite direction than 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 compared with smokers. Overall, the implications of this study are unclear. First, because the study is not using a cross-over 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 autonomic 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 compared with non-users, heart rate variability was measured with an echocardiogram (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 PREPUBLICATION COPY: UNCORRECTED PROOFS

9-14 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES 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 to HF ratio were significantly increased (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-to-HF ratio during the control 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. CONCLUSIONS The level of evidence regarding the association between e-cigarette use and biomarkers of cardiovascular disease risks varies: Conclusion 9-2. There is substantial evidence that heart rate increases shortly after nicotine intake from e-cigarettes. Conclusion 9-3. There is moderate evidence that diastolic blood pressure increases shortly after nicotine intake from e-cigarettes. Conclusion 9-4. There is limited evidence that e-cigarette use is associated with a short-term increase in systolic blood pressure, changes in biomarkers of oxidative stress, increased endothelial dysfunction and arterial stiffness, and autonomic control. Conclusion 9-5. There is insufficient evidence that e-cigarette use is associated with long-term changes in heart rate, blood pressure, and cardiac geometry and function. PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-15 TABLE 9-1 Clinical Studies of Short-Term Effects of Electronic Cigarette (EC) Use on Cardiovascular Endpoints First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC St. Helen, Not blinded Healthy sole and - 32.3 y KangerTech Mini Ad lib Before and at 14 HR (bpm) Mean max change 2017a 3-arm dual e-cigarette - 79% ProTank 3 acclimatization 5, 10, 15, 20, (SEM) in HR after randomized user (less 5 - 14.3% clearomizer (1.5 from 4 to 10 pm, and 30 min 15 puffs versus cross-over cigarettes/day - 71.4% ohm) connected to abstinent after the final baseline was: trial over 3 from colleges - 0% a KangerTech 3.7 overnight, 15 puff of: 17.2 (2.5) consecutive campuses in San V, 1,000 mAh puffs session (1 Strawberry (strawberry) days (in Francisco, CA battery every 30”) Tobacco 12.3 (2.3) patient) 3 flavors: Bulk e- followed by 4h Own flavor (tobacco) juice strawberry abstinence and 9.4 (2.4) (own (pH 8.29) then 90-min ad lib flavor) Bulk e-juice Mean max Mean maximum tobacco (pH 9.10) nicotine increase (95% CI) Own flavor (mean concentration was was 4.6 (0.8, 8.5) pH 6.80) with 12.1 (2.0), 9.5 bpm higher for 50/50 PG/ (1.2) and 6.2 (1.0) strawberry e-liquid glycerol and 18 ng/ml for than for tobacco e- mg/ml nicotine strawberry, liquid (for strawberry and tobacco, and own tobacco) flavor, Mean (SEM) of respectively heart rate area under the curve (AUC) after 15 puffs was 245 (37) (strawberry) 210 (45) (tobacco) 169 (53) (own) Mean difference (95% CI) in HR PREPUBLICATION COPY: UNCORRECTED PROOFS

9-16 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC AUC: 34 (-43, 111) comparing strawberry to tobacco No difference in HR by pH of the e- liquid, mean (SEM) 183 (85) v. 154 (69) for usual acidic and usual basic pH (p-value 0.85) HR not reported for the ad lib session Spindle, Not blinded Healthy e-sole and - 29.6 y Own e-cigarette 10 puffs, 30” Before and 29 HR (bpm) Mean (SEM) HR 2017b 2-arm dual e-cigarette -76% device and e-liquid interpuff interval continually increased to 73.3 ordered users ( 5 tobacco -7% ( 12 mg/ml and 90-min ad every 20” for (1.3) bpm after the cross-over cigarettes/ per day)-NR nicotine) libitum bout 2.5 h directed bout and trial with a from Richmond, - 0% Plasma nicotine comparing to 73.9 (1.5), 73.6 minimum of VA using e-cigs fo increased up to 4.6 same device (1.6), and 74.4 48h at least 3 months ng/ml during ad lib and e-liquid (1.7) at 30, 60, and washout with or 90 min. after the period without a onset of the ad lib mouthpiece but compared with baseline (66.3 (1.3) bpm) PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-17 First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC St.Helen, 1-arm trial Healthy sole and -38.4 y Usual brand of 15 puffs session, Before and 5, 13 HR (bpm) Compared with 2016c dual e-cigarette - 54% device and e-liquid 30” interpuff 10, 15, 20, and baseline HR users (less 5 -23% interval, followed 30 min after increased a mean cigarettes/day) -NR by 4h abstinence the final puff of 8.0 (p < 0.001) -0% and then 90-min and 5.2 (p = 0.04) ad lib bpm after 5 and 10 Mean plasma minutes, nicotine after 15 respectively, and puffs was 8.4 was not ng/ml significantly different after 15 minutes PREPUBLICATION COPY: UNCORRECTED PROOFS

9-18 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Carnevale, Single Healthy smoking - 28.0 y NR leading brand 1 cigarette Just before-30 40 Mean (SD) before 2016 d blinded 2- and never - 47.5% charged 9 puffs (equivalent min. after Serum sNOX2-dp and after cig / e- arm ordered smoking - 50% 16 mg nicotine to 0.6 mg of - 1 cigarette (pg/ml) cig cross-over participants from - 0% cartridge (~250 nicotine) - 9 EC puffs 8-isoPGF2 23.6(7.8) 38.2(9.9) trial with 1 Rome, Italy - NR puffs) cotinine NR (pmol/L) / 21.6(6.8) week (recruitment Serum NO 30.2(6.2) washout dates NR) ( M) Serum vitamin E 135(56) 203(81) / ( mol/mmol) 133(54) 187(62) Brachial artery FM (%) 35.3(12.0) 19.5(9.9) / 35.5(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 PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-19 First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Antoniewicz, Single Healthy sporadic - 28 y eGo XL (2nd 10 puffs in 10 min Before and 1, 16 EPC (leukocytes EPCs increased 2016e blinded 2- smokers from - 64.3% generation), 1100 in semisupine 4, and 24h events) after e-cig use at 1 arm Stockholm, Sweden 100% - mAh, 3.7V, dual position after: h (p = 0.003) and randomized not smoking in the - 0% coil CE5 atomizer Median (IQR) - EC 4h (p = 0.036) and cross-over last 7 days - 100% E-liquid w nicotine plasma cotinine - control Microvesicles returned to normal trial with 1- (recruitment dates 12 mg/ml, PG/ after 4h was 4.1 (resting) (number) all and at 24h. No changes week NR) glycerol (3.5,4.7) ng/ml by origin were observed for washout 49.4/44.4% (endothelial, control periods without flavors platelet or (Valeo laboratories leukocytes) and Median (IQR) pre, GmbH) inflammation 1, 4, 24h e- markers cig/control (HMGB1, p- 1,725(731,4012), Selectin, CD40, 2,600(1264,7668), and E-selectin 5,102(2164,7858), [CD62E]) 5,731(1402,7176) /1,557(1020,4997), 3,277(2038,4987), FeNO (only pre 3,700(2545,4494), and 24h) 2,724(2012,4858) 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). PREPUBLICATION COPY: UNCORRECTED PROOFS Median (IQR) pre, 24 h e-cig/controls 10 (7,15), 11 (8 14) / 10 (7 15)

9-20 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Fogt, 2016f Double Healthy participant- 23.1 (2.5) Green Smart 20 puffs in 10 min 40 min. post 20 Resting Mean (SD) 0 / 18 blinded, 2- from San Antonio, - 50% Living EC (details inhaling as deeply exposure: SBP (mmHg) mg/ml EC arm ordered TX (recruitment - 0% not described) as possible - EC 0 mg/ml DBP (mmHg) 115.8 (8.0) / 112.1 crossover dates NR) - NR E-liquid with 0 and Urine cotinine 0- - EC 18 mg/ml HR (bpm) (6.8) p = 0.04 trial with 1 - 100% 18 mg/ml nicotine 10 and 30-100 RMR (kcal/min) 73.6 (8.3) / 76.6 week ng/ml for 18 and 0 Exercise test VO2 (L/min) (6.0) p = 0.04 washout mg/ml EC, starts 55 min RQ (Energy exp.) 61 (10) / 61 (10) p respectively post EC Exercise test = 0.47 exposure SBPpeak (mmHg) 1.19 (0.2) / 1.18 DBPpeak (mmHg) (0.2) p = 0.39 VO2peak (L/min) 0.25 (0.1) / 0.25 Power (W)peak (0.2) p = 0.5 0.79 (0.01) / 0.78 (0.1) p = 0.15 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-21 First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Cooke, Double Healthy non- - 23 (1) Green Smart 20 puffs in 10 min Before and 20 Seated Change pre-post 0 2015g blinded, smoking - 50% Living EC (details Urine cotinine 0- 10-20 SBP (mmHg) / 18 mg/ml** randomized, participants from - 0% not described) 10 and 30-100 (seated), 20- DBP (mmHg) 2 / 2 (p 0.03) 2-arm San Antonio, TX - NR E-liquid with 0 and ng/ml for 18 and 0 25 (supine), HR (pbm) 2 / 4 (p = 0.001) crossover (recruitment dates -100% 18 mg/ml nicotine mg/ml EC, 25-30 (70° Supine, tilt, and 4 / 1.2 (p 0.03) trial with 1- NR) respectively head-up tilt), recovery positions week and 30-35 (5 min each): Mean BP in each washout (supine) min. SBP (mmHg) position 0 / 18 post exposure: DBP (mmHg) mg/ml** - EC 0 mg/ml Autonomic control 109/117 p = NR, - EC 18 mg/ml R-R 99/108 p = 0.03, RRISD 110/118 p = NR 1-week 62/69 p = 0.02, washout 61/67 p = 0.02, period 64/71 p = 0.04 R-R and RRISD decreased with tilt (p 0.01), but reductions were similar by treatment group PREPUBLICATION COPY: UNCORRECTED PROOFS

9-22 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Yan, 2015 h Single Healthy - 38.7 blu ECs with the EC: 50 5s puffs at 30 min pre 23 Change (SD) post blinded, participants - 48% following e-liquid 30s intervals and 20 min SBP (mmHg) versus randomized smoking in past -100% formula-tions Cigarette: usual following the pretreatment: 6-arm 12 months from - 0% A: classic EC 2.4% puff duration at end of the ad A: 1.1 (11.1) p = crossover Lincoln, NE and - 0% nic. 75% glycerol 30s intervals lib period of 0.63 / B: 2.8 (11.3) trial with after a lead-in B: classic EC 2.4% EC and cigarette: EC A, B, C, DBP (mmHg) p = 0.24 / C: 4.0 36h period for 7 days nic. 50/20% 1-h ad lib use D, E, and (10.0) p = 0.07 / washout to get accustomed glycerol/ Plasma nic. F (Marlboro D: 5.8 (10.0) p = period to using EC PG (ng/ml) ranged cigarette) 0.02 / E: 3.8 (10.7) products and C: menthol EC, from 2.0 (D) to 3.0 HR (bpm) p = 0.10 / F: 5.7 abstaining from 2.4% nic. 75% (B) at 5 min, from (12.4) p = 0.04 nicotine for 36 h glycerol 10.0 (D) to 17.1 D: classic EC 1.6% (B) at 30 min and A: 6.8 (6.7) p < nic. from 13.7 (D) to 0.001 / B: 6.8 (6.5) 75% glycerol 22.4 (B) after 1 p < 0.001 / C: 3.2 E: classic EC 1.6% extra h ad lib. For (7.3) p = 0.05 / D: nic. 50/20% cigarette it was 6.8 (3.8) p < 0.001 glycerol/ 14.4, 7.9, and 29.2 / E: 4.4 (4.7) p < PG at the same times 0.001 / F: 6.8 (7.1) p < 0.001 A: 2.3 (5.5) p = 0.06 / B: 3.6 (6.0) p = 0.008 / C: 4.1 (5.7) p = 0.002 / D: 1.9 (7.4) p = 0.24 / E: 2.2 (5.9) p = 0.08 / F: 4.3 (5.4) p = 0.001 Plasma nicotine positively correlated with HR change with a PREPUBLICATION COPY: UNCORRECTED PROOFS mean increase of 0.16 bpm for 1 ng/ml increase in l i ti

CARDIOVASCULAR DISEASE 9-23 First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Szo tysek- Single Healthy students of- 23 (2) Ego-3 (clearomizer 1h sessions: 10 minutes 15 Arterial stiffness: Mean (95% CI) Bo dys, blinded, 2- University of - 0% Crystal 2 with coil, Cigarette 10-12 after: SI (m/s) before and after 2014i arm ordered Silesia, Poland - 100% 2.4 Ohm, voltage puffs (personal - Cigarette cigarette / EC cross-over smoking > 5 - 0% battery 900 mAh, brand) - EC RI (%) SI: 6.75 (6.66, trial with 1- cig/day for 2 years - 0% 3.4 V) EC 15 puffs 6.85), 6.56 (6.46, day and used EC at leas nicotine 24 mg/ml Cotinine NR SBP (mmHg) 6.65) p = 0.006 / washout 10 times DBP (mmHg) 6.73 (6.62, 6.84), period HR (bpm) 6.75 (6.66, 6.83) p = NS RI: 54.0 (51.5, 56.7), 49.6 (47.5, 51.8) p = 0.01 / 52.0 (49.3, 54.7), 50.8 (48.2, 53.3) p = NS Both cigarettes and EC showed a small increase in SBP, DBP, and HR, but it was not significant (only figure) and was hard to see PREPUBLICATION COPY: UNCORRECTED PROOFS

9-24 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Farsalinos, Not Healthy -35 (5) eGO-T battery Combustible Before and 36 / Mean (SD) change 2014 j blinded, 2- consecutive - 90% (Nobacco, Greece) tobacco cigarette after the 40 SBP (mmHg) before after arm ordered smokers at Onassis - 47% with an eGo-C smoked ad lib. experiments DBP (mmHg) cigarette / EC trial with no Cardiac Surgery - 53% atomizer (2nd EC ad lib for 7 - Cigarette HR (bpm) 6.6 (5.2) p < 0.001 smoking or Center, Greece (> - NA generation) 650 minutes - EC Echocardiography / 0.7 (4.6) p = 0.37 nicotine use 14 cig/day for 5 mAh recharge-able Cotinine NR E (cm/s) 4.4 (3.3) p < 0.001 in the 4h years) and EC user lithium battery, 3.5 A (cm/s) / 3.0 (3.6) p < before the who quit smoking volts manually Experiments for E/A 0.001 intervention and used 9-12 activated EC and cig were DT (ms) 5.9 (4.7) p < 0.001 mg/ml nicotine e- 11 mg/ml nicotine done in different IVRT (ms) / 0.4 (4.8) p = liquid for 1 mont PG > 60%, linalool rooms IVRTc (ms) 0.649 (mean 6 < 5%, tobacco MPI months).Smokers essence < 5%, Sm (cm/s) 0.6 (6.1) p = 0.57 and EC users methyl vanillin < Em (cm/s) / 1.2 (5.0) p = 0.13 similar at baseline 1%. Am (cm/s) 2.9 (5.7) p = 0.007 except EC used to Em/Am / 1.6 (5.6) p = 0.08 smoke 10 cig/d E/Em 0.10 (0.16) p = more when they MPIt 0.001 / 0.03 smoked than GS (%) (0.14) p = 0.17 current smokers SRs (s-1) 3 (10) p = 0.09 / 1 SRe (s-1) (8) p = 0.58 SRa (s-1) 5.6 (9.2) p < 0.001 / 1.0 (5.7) p = 0.28 10.4 (10.1) p < 0.001 / 1.2 (6.9) p = 0.29 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 PREPUBLICATION COPY: UNCORRECTED PROOFS = 0.10 0.1 (0.6) p = 0.80 / 0.2 (0.8) p = 0.12 0 08 (0 13)

CARDIOVASCULAR DISEASE 9-25 First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Czoga a, Not Healthy daily - 34.9 (15.3) MILD M2001 (1st Ad lib e-cig use - Cigarette 42 SBP (mmHg) Mean (SD) before 2012 k blinded, 2- cigarette smokers - 50% generation) 14 (minimum amount - EC DBP (mmHg) and after cigarette / arm ordered (5 cigarettes per - 100% mg/ml nicotine of puffs NR) HR (bpm) e-cigarette cross-over day or more) - 0% SBP: 127.1 (15.4) study with from Sosnowiec, - 100% L&M blu label PM to 131.4 (NS) / 1-week Poland cigarette 122.6 (11.4) to washout 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) Eissenberg, Not Healthy smokers - 29.8 y NPRO (NJOY) Instructed to puff Before and up 16 HR (bpm) HR increased only 2010 l blinded, 4- from Richmond, - 69% and Hydro (Crown and then puffed ad o 30 min. after after own cigarette arm ordered Virginia with 12 - 100% Seven) lib 10 times (30-s 1st puff: (p < 0.05). trial with hours of - 0% 16 mg nicotine interval) for each Cigarette (own) Numbers are not washout tobacco/nicotine -100% cartridge menthol product, cycle was Sham puffing shown in the paper period of 48 abstinence or non-menthol repeated 60 min NPRO for either cigarette h confirmed with CO (choice of later Hydro or EC < 10 ppm. participant) Plasma nicotine (ng/ml) for own cigarette, NPRO and Hydro was 16.8, 3.5, and 2.5 at 5 min and 8.7, 2.6, and 2.2 at 30 min PREPUBLICATION COPY: UNCORRECTED PROOFS

9-26 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES First Study Population Mean Age EC device - Intervention Comparison N* Study endpoints Results Author, Design % Men characteristics pattern groups Year % C-smk E-Liquid - Cotinine levels % F-smk % Naïve EC Vansickel, Not Healthy smokers - 33.6 y NPRO (18-mg, Instructed to puff aBefore and up 32 HR (bpm) HR increased from 2010m blinded, from Richmond, - 59% NJOY) 10 times with to 1h after: 66 ppm before the randomized VA with 12 hours - 100% Hydro (16-mg) 30seconds interval Cigarette (own) experiment to 80, 4 arm trial of tobacco/nicotine- 0% at 2 separate times Sham 75, and 70 ppm 5, with abstinence - 100% during the session Puffing NPRO 15, and 30 min. washout confirmed with CO (1h between them) and Hydro after the 1st period of < ppm experiment and to 48h Plasma nicotine 74, 73, and 70 ppm increased for own after the 2nd brand but not for experiment with NPRO, Hydro, and the cigarette own sham experiments brand. For NPRO and Hydro, only small changes not statistically significant were observed (from 66 ppm before to a maximum of 69 ppm at 5 after the 1st experiment and 67 ppm at 5 min after the 2nd experiment with NPRO; and even smaller changes with Hydro NOTES: 8-isoPGF2 : 8-iso-prostaglandin F2 ; EC: electronic cigarette; EPC: endothelial progenitor cells; FMD: flow-mediated dilation; LA: left atrial; LV: left ventricle; MSNA: efferent 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-27 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. * Final sample size used in the analyses. For Antoniewicz and colleagues (2016), 2 participants 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 ** Numbers approximated because abstracted from a figure. SOURCES: a St.Helen et al., 2017 b Spindle et al., 2017. c St.Helen et al., 2016. d Carnevale et al., 2016. e Antoniewicz et al., 2016. f Fogt et al., 2016. g Cooke et al., 2015. h Yan and D’Ruiz, 2015. i Szo tysek-Bo dys et al., 2014. j Farsalinos et al., 2014. k Czogala et al., 2012. l Eissenberg, 2010. m Vansickel et al., 2010. PREPUBLICATION COPY: UNCORRECTED PROOFS

9-28 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 9-2 Epidemiologic Studies on Chronic E-Cigarette (EC) Use and Cardiovascular Endpoints - Age Range - % Men EC Pattern First - % C- EC Device of Use and Author, Study Population smk CharacteristCotinine Compariso Study Year Design - % F-smk ics Levels n Groups N* Endpoints Results Adjustment** Moheimani, XS Los Angeles, - 21-45 y NR - mean 241 - EC users 16 / SBP (mmHg) Mean 115.8 / 109.0 (p = None (e-cig 2017a CA recruited - 59% min/day - No users 18 DBP (mmHg) 0.07) users more in 2015-2016 - 0% - mean 1.6 y MAP (mmHg) 73.5 / 70.0 (p = 0.27) likely to be (source or - 35% - range EC users HR (bpm) 87.6 / 83.0 (p = 0.15) men and recruitment plasma asked not to HRV: HF (nu) 64.0 / 63.0 (p = 0.73) former methods NR) cotinine: use the e- LF (nu) 46.5 / 57.8 (p = 0.04) smokers) 2.6 to 27.3 cigarette the LF/HF 52.7 / 39.9 (p = 0.03) mg/L day of the HRV-control Br. 1.37 / 0.85 (p = 0.05) study NS (no. not shown) 12 / oxLDL (U) 18 paraxonase-1 3801 / 2413 (p = 0.01) (nmol) 649.9 / 892.8 (p = 0.17) HDLantiox.index 0.42 / 0.38 (p = 0.55) (U 270.9 / 251.9 (p = 0.24) Fibrinogen (mg/d 3 / 1 (p = 0.15) CRP (#abnormal) Correlations plasma cotinine with: HF ( 0.34, p = 0.04) LF (0.35, p = 0.03) LF/HF (0.36, p = 0.03) oxLDL (0.35, p = 0.05) other biomarkers (NS) Farsalinos, RCT also Smokers not - mean “Categoria” NR RCT arms: SBP (mmHg) RCT: mean (SD) SBP Some analyses 2016b analyzed attempting to 44.0y EC model - 0% nicotine63 / DBP (mmHg) decreased from 128 (15) at adjusted for as a CO quit from - 63% 401, Arbi - 1.8% 66 / HR (bpm) baseline to 123 (14) mmHg sex, age, and Catania, - 100% Group Srl - 2.4% 61 at baseline and at 52 weeks (p = 0.004) with weight change PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-29 - Age Range - % Men EC Pattern First - % C- EC Device of Use and Author, Study Population smk CharacteristCotinine Compariso Study Year Design - % F-smk ics Levels n Groups N* Endpoints Results Adjustment** Italy - 0% (disposable at 8 follow-up no difference by treatment followed for cartridge and CO groups: visits over 52 group 52 weeks, 3.7 V-90 - Smokers 93 / weeks recruited in mAh - Dual users 34 / CO: adjusted mean change 2010-2011 lithium-ion - Sole users 18 (95% CI) in SBP over time through a battery) (called compared with smokers: smoking E-liquid failures, Dual users: 6.76 ( 13.39, cessation Nic: reducers, 0.13) mmHg clinic and - 2.4% 12 wk and quitters END users: 14.25 ( 23.70, offered to - 2.4% 6 wk in the 4.81) mmHg use e-cigs + 1.8% 6 paper) wk Stratified analysis by - 0% 12 wk baseline BP§: 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. 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) PREPUBLICATION COPY: UNCORRECTED PROOFS

9-30 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES - Age Range - % Men EC Pattern First - % C- EC Device of Use and Author, Study Population smk CharacteristCotinine Compariso Study Year Design - % F-smk ics Levels n Groups N* Endpoints Results Adjustment** Polosa, 2016c CO Regular - mean 53.9 NR Daily use - Smokers 46 / SBP (mmHg) Median (IQR) Sex, age, smokers on y from 10 to - Dual users 23 / DBP (mmHg) 145(137,152)/137(132,144)/ weight, treatment for - 56% 14 months - Single 20 HR (bpm) 134(130,142) changes in hypertension - 48% (83.7% more users Measured at 87(85,90) / 83(80,92) / SBP between at an (some dual than 12 baseline, 6 and 81(74,84) prebaseline outpatient users) months) 12 months 78(72,85) / 77(70,83) / and baseline < clinic in - 52% 80(75,86) 10 mmHg Catania, Italy (period 145(136,150)/130(121,140)/ of %HT control 130(123,138) recruitment smokers / ENDs 85(85,90) / 80(71, 90) / NR) users 80(75,87) 79(72,84) / 76(71,92) / 80(76,90) p-value comparing ENDs 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 NOTES: c-smk = current smoker; CO = cross-over; DBP = diastolic blood pressure; f-smk = former smoker; HF = high frequency; HR = heart rate; HRV = heart rate variability; 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. * 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 were excluded because of active smoking, and 2 and 5 e-cigarette users were excluded because of active smoking or because of e-cigarette use the day of the study, respectively. Also, only 12 e-cigarette users had sufficient bio-specimens available to measure biomarkers. PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-31 For Farsalinos 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). ** Adjustment for potential confounding through regression modeling, matching, stratification, or other strategy. § Elevated BP defined as SBP/DBP greater than or equal to 130/85 mmHg. SOURCES: a Moheimani et al., 2017. b Farsalinos et al., 2016. c Polosa et al., 2016. PREPUBLICATION COPY: UNCORRECTED PROOFS

9-32 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES REFERENCES Anderson, C., A. Majeste, J. Hanus, and S. Wang. 2016. E-cigarette aerosol exposure induces reactive oxygen species, DNA damage, and cell death in vascular endothelial cells. Toxicological Sciences 154(2):332-340. Antoniewicz, L., J. A. Bosson, J. Kuhl, S. M. Abdel-Halim, A. Kiessling, F. Mobarrez, and M. Lundback. 2016. Electronic cigarettes increase endothelial progenitor cells in the blood of healthy volunteers. Atherosclerosis 255:179-185. Benowitz, N. L., and J. B. Fraiman. 2017. Cardiovascular effects of electronic cigarettes. Nature Reviews Cardiology 14(8):447-456. Bhatnagar, A. 2016. E-cigarettes and cardiovascular disease risk: Evaluation of evidence, policy implications, and recommendations. Current Cardiovascular Risk Reports 10(7):24. Carnevale, R., S. Sciarretta, F. Violi, C. Nocella, L. Loffredo, L. Perri, M. Peruzzi, A. G. M. Marullo, E. De Falco, I. Chimenti, V. Valenti, G. Biondi-Zoccai, and G. Frati. 2016. Acute impact of tobacco vs. electronic cigarette smoking on oxidative stress and vascular function. Chest 150(3):606-612. Cooke, W. H., A. Pokhrel, C. Dowling, D. L. Fogt, and C. A. Rickards. 2015. Acute inhalation of vaporized nicotine increases arterial pressure in young non-smokers: A pilot study. Clinical Autonomic Research 25(4):267-270. Cosselman, K. E., A. Navas-Acien, and J. D. Kaufman. 2015. Environmental factors in cardiovascular disease. Nature Reviews Cardiology 12(11):627-642. Czogala, J., M. Cholewinski, A. Kutek, and W. Zielinska-Danch. 2012. [evaluation of changes in hemodynamic parameters after the use of electronic nicotine delivery systems among regular cigarette smokers]. Przegl Lek 69(10):841-845. Czogala, J., M. L. Goniewicz, B. Fidelus, W. Zielinska-Danch, M. J. Travers, and A. Sobczak. 2014. Secondhand exposure to vapors from electronic cigarettes. Nicotine & Tobacco Research 16(6):655-662. Eissenberg, T. 2010. Electronic nicotine delivery devices: Ineffective nicotine delivery and craving suppression after acute administration. Tobacco Control 19(1):87-88. Farsalinos, K. E., D. Tsiapras, S. Kyrzopoulos, M. Savvopoulou, and V. Voudris. 2014. Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: Comparison with the effects of regular cigarettes. BMC Cardiovascular Disorders 14. Farsalinos, K., F. Cibella, P. Caponnetto, D. Campagna, J. B. Morjaria, E. Battaglia, M. Caruso, C. Russo, and R. Polosa. 2016. Effect of continuous smoking reduction and abstinence on blood pressure and heart rate in smokers switching to electronic cigarettes. Internal and Emergency Medicine 11(1):85-94. Fogt, D. L., M. A. Levi, C. A. Rickards, S. P. Stelly, and W. H. Cooke. 2016. Effects of acute vaporized nicotine in non-tobacco users at rest and during exercise. International Journal of Exercise Science 9(5):607-615. HHS (U.S. Department of Health and Human Services). 2014. The health consequences of smoking-50 years of progress: A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. PREPUBLICATION COPY: UNCORRECTED PROOFS

CARDIOVASCULAR DISEASE 9-33 James, P. A., S. Oparil, B. L. Carter, and et al. 2014. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8). Journal of the American Medical Association 311(5):507-520. Koskela, J. K., A. Tahvanainen, A. Haring, A. J. Tikkakoski, E. Ilveskoski, J. Viitala, M. H. Leskinen, T. Lehtimaki, M. A. Kahonen, T. Koobi, O. Niemela, J. T. Mustonen, and I. H. Porsti. 2013. Association of resting heart rate with cardiovascular function: A cross- sectional study in 522 Finnish subjects. BMC Cardiovascular Disorders 13:102. Lekakis, J., P. Abraham, A. Balbarini, A. Blann, C. M. Boulanger, J. Cockcroft, F. Cosentino, J. Deanfield, A. Gallino, I. Ikonomidis, D. Kremastinos, U. Landmesser, A. Protogerou, C. Stefanadis, D. Tousoulis, G. Vassalli, H. Vink, N. Werner, I. Wilkinson, and C. Vlachopoulos. 2011. Methods for evaluating endothelial function: A position statement from the European Society of Cardiology working group on peripheral circulation. European Journal of Cardiovascular Prevention and Rehabilitation 18(6):775-789. Lerner, C. A., I. K. Sundar, H. Yao, J. Gerloff, D. J. Ossip, S. McIntosh, R. Robinson, and I. Rahman. 2015. 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 10(2):e0116732. Levenson, J., A. C. Simon, F. A. Cambien, and C. Beretti. 1987. Cigarette smoking and hypertension. Factors independently associated with blood hyperviscosity and arterial rigidity. Arteriosclerosis, Thrombosis, and Vascular Biology 7(6):572. Mahmud, A., and J. Feely. 2003. Effect of smoking on arterial stiffness and pulse pressure amplification. Hypertension 41(1):183. Mattace-Raso, F. U. S., T. J. M. van der Cammen, A. Hofman, N. M. van Popele, M. L. Bos, M. A. D. H. Schalekamp, R. Asmar, R. S. Reneman, A. P. G. Hoeks, M. M. B. Breteler, and J. C. M. Witteman. 2006. Arterial stiffness and risk of coronary heart disease and stroke. Circulation 113(5):657. McEniery, C. M., S. Wallace, I. S. Mackenzie, B. McDonnell, Yasmin, D. E. Newby, J. R. Cockcroft, and I. B. Wilkinson. 2006. Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans. Hypertension 48(4):602. Moheimani, R. S., M. Bhetraratana, F. Yin, K. M. Peters, J. Gornbein, J. A. Araujo, and H. R. Middlekauff. 2017. Increased cardiac sympathetic activity and oxidative stress in habitual electronic cigarette users: Implications for cardiovascular risk. JAMA Cardiology. Nigra, A. E., A. Ruiz-Hernandez, J. Redon, A. Navas-Acien, and M. Tellez-Plaza. 2016. Environmental metals and cardiovascular disease in adults: A systematic review beyond lead and cadmium. Current Environmental Health Reports 3(4):416-433. Poirier, P. 2014. Exercise, heart rate variability, and longevity: The cocoon mystery? Circulation 129(21):2085-2087. Polosa, R., J. B. Morjaria, P. Caponnetto, E. Battaglia, C. Russo, C. Ciampi, G. Adams, and C. M. Bruno. 2016. Blood pressure control in smokers with arterial hypertension who switched to electronic cigarettes. International Journal of Environmental Research and Public Health 13(11):E1123. Pope, C. A., 3rd, R. T. Burnett, D. Krewski, M. Jerrett, Y. Shi, E. E. Calle, and M. J. Thun. 2009. Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: Shape of the exposure-response relationship. Circulation 120(11):941-948. PREPUBLICATION COPY: UNCORRECTED PROOFS

9-34 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Spindle, T. R., M. M. Hiler, A. B. Breland, N. V. Karaoghlanian, A. L. Shihadeh, and T. Eissenberg. 2017. The influence of a mouthpiece-based topography measurement device on electronic cigarette user’s plasma nicotine concentration, heart rate, and subjective effects under directed and ad libitum use conditions. Nicotine & Tobacco Research 19(4):469-476. St.Helen, G., K. C. Ross, D. A. Dempsey, C. M. Havel, P. Jacob, 3rd, and N. L. Benowitz. 2016. Nicotine delivery and vaping behavior during ad libitum e-cigarette access. Tobacco Regulatory Science 2(4):363-376. St.Helen, G., D. A. Dempsey, C. M. Havel, P. Jacob, 3rd, and N. L. Benowitz. 2017. Impact of e-liquid flavors on nicotine intake and pharmacology of e-cigarettes. Drug and Alcohol Dependence 178:391-398. Szo tysek-Bo dys, I., A. Sobczak, W. Zieli ska-Danch, A. Barto , B. Koszowski, and L. Ko mider. 2014. Influence of inhaled nicotine source on arterial stiffness. Przeglad lekarski 71(11):572-575. Vansickel, A. R., C. O. Cobb, M. F. Weaver, and T. E. Eissenberg. 2010. A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: Nicotine delivery profile and cardiovascular and subjective effects. Cancer Epidemiology, Biomarkers & Prevention 19(8):1945-1953. Willum Hansen, T., J. A. Staessen, C. Torp-Pedersen, S. Rasmussen, L. Thijs, H. Ibsen, and J. Jeppesen. 2006. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 113(5):664. Yan, X. S., and C. D’Ruiz. 2015. Effects of using electronic cigarettes on nicotine delivery and cardiovascular function in comparison with regular cigarettes. Regulatory Toxicology and Pharmacology 71(1):24-34. PREPUBLICATION COPY: UNCORRECTED PROOFS

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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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