Commentary

E-cigarettes and CV risk: Current state of the evidence for cardiologists

Electronic cigarettes include a diverse group of battery-powered devices that vaporize nicotine-containing, often flavored solvents for inhalation. Initially, these devices were proposed as an alternative cessation strategy for cigarette smokers who are unable to quit using conventional cessation therapies.

However, since their introduction into the U.S. market in 2006, e-cigarettes have gained popularity, especially among youth, and their use (also called vaping) has considerably extended to “never smokers.” In a recent study, it was estimated that as of 2016, almost 2 million U.S. adults who had never smoked cigarettes were current users of these products. With the recent introduction of newer brands (eg, Juul), which can be used more discreetly among teenagers, evidence suggests that e-cigarette use prevalence has trended upward, particularly in youth.

Olusola A. Orimoloye

In 2016, the FDA extended its regulatory authority to e-cigarettes through the Deeming Rule. However, to guide further regulation of these products in adults, the FDA requires actionable evidence on their health effects, including any potential CV toxicity.

Mohammadhassan Mirbolouk

Vaping and cardiotoxicity

There are many constituent components of inhaled e-cigarette vapor that may be potential candidates for CV toxicity (Table). These include toxic metals such as lead, nickel and chromium; volatile organic compounds (VOCs) such as acrolein, flavoring derivatives; and nicotine, a known trigger for myocardial ischemia and infarction due to stimulation of the sympathetic nervous system. Comparative studies of VOC exposure across a range of tobacco product use behaviors suggest that sole e-cigarette users have significantly greater levels of exposure to VOCs than nonusers of tobacco products, albeit lower than in conventional cigarette smokers.

Michael J. Blaha

Given the popularity of e-cigarette use and the aforementioned concerns about potential CV toxicity, there has therefore been considerable interest in understanding CV risks that may attend the use of these products, in absolute terms, and relative to conventional cigarette smoking.

E-cigarettes and CV risk

Unfortunately, according to the 2018 report of the National Academies of Sciences, Engineering, and Medicine, titled “Public Health Consequences of Electronic Cigarette Use,” there is, as yet, no available evidence as to whether e-cigarette use is associated with clinical CV outcomes such as CHD, peripheral artery disease or stroke, and subclinical disease, including carotid intima-media thickness and coronary artery calcification.

Despite the general availability of laboratory-based animal studies, and short-term exposure studies that have highlighted unfavorable effects of e-cigarette exposure on short-term outcomes such as heart rate variability, oxidative stress and endothelial dysfunction, critical prospective epidemiologic data are sparse (Table).

There are many contributory factors to the paucity of such data. First, most e-cigarette users are young people who have very low baseline risk for subclinical or clinical CVD outcomes. Secondly, given the temporal proximity of their introduction into the market, it is possible that most users have not used these products for long enough to reasonably accumulate excess risk. Finally, the overall pattern of use of these products is immensely variable, with many users cycling rapidly between e-cigarettes and other tobacco products, experimenting with their use, being occasional users, or settling into the use of multiple products. Indeed, studies show that dual use of e-cigarettes and conventional cigarettes is the predominant pattern of e-cigarette use.

Potential relationships

In the absence of longitudinal data, two cross-sectional studies assessing associations between e-cigarette use and classical CVD outcomes have been conducted. In the most recent of these studies, Albert D. Osei, MD, MPH, postdoctoral researcher at the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, and colleagues examined the association between self-reported use of e-cigarettes and a CVD composite of angina, MI and stroke using data from about 450,000 participants of the Behavioral Risk Factor Surveillance System, a large nationally representative sample of U.S. adults.

The researchers found no significant association between e-cigarette use and CVD among never smokers, but they reported a statistically significant 36% higher odds of CVD in dual users of e-cigarettes and conventional cigarettes compared with those who only used conventional cigarettes. Additionally, the authors showed a graded increase in odds of CVD with increasing frequency of e-cigarette use, reporting significantly greater odds in daily users than in occasional users.

The effect of confounding and reverse causality may be difficult to exclude in their study, but it represents a crucial first step to understanding potential CV risks that e-cigarettes may pose.

Ongoing studies in the e-cigarette/CVD space are looking to explore the relationship between e-cigarette use and mediators of CV risk, which are known to appear early in the atherosclerotic process. Some of these include inflammatory markers, markers of oxidative stress and measures of vascular reactivity. Assessment of the relationship between e-cigarette use and these relatively proximal measures may help to address confounding in prior human studies and to inform regulatory and clinical decision-making.

Implications for clinicians

Current evidence suggests that e-cigarettes may be useful as cessation aids, but with important drawbacks. A recent multicenter, pragmatic trial by Peter Hajek, PhD, professor of clinical psychology and director of the Health and Lifestyle Research Unit at the Wolfson Institute of Preventive Medicine at Queen Mary University of London, and colleagues found e-cigarettes to be more effective for smoking cessation than nicotine replacement therapy (18% abstinence rate in e-cigarette-users vs. 9.9% abstinence rate in nicotine replacement therapy users) during a 1-year period, when both products were accompanied by behavioral support. However, it is important to interpret these results in the context of the differential pattern of long-term use observed among e-cigarette users in the study. Although 80% of those who “quit” smoking using e-cigarettes were still using e-cigarettes, only 9% of those who quit using nicotine replacement therapy were still on therapy at the end of the study. This finding raises significant concerns about the likelihood and implications of long-term use and continued addiction to nicotine in those who quit smoking using e-cigarettes.

In the context of paucity of data about long-term consequences of e-cigarette exposure, it is important for clinicians to carefully weigh the potential risks of sustained use of these products against short-term benefits of cigarette smoking cessation, and to only recommend these products (with caution) when first-line options such as FDA-approved cessation therapies have been exhausted.

Longitudinal studies needed

The popularity of e-cigarettes has increased over time, but very little is known about CV risks that may be associated with their use. Nevertheless, since evidence suggests elevated levels of exposure to potential cardiotoxic substances in e-cigarette users compared with never users of tobacco products, it is reasonable to conclude that e-cigarette use in nonsmoking youth is almost certainly harmful, and should be discouraged.

Crucially, longitudinal studies are needed to definitively assess potential CV harm that may attend the use of these products, as the few studies that have demonstrated associations between e-cigarette use and clinical outcomes such as CHD and stroke have been limited by their cross-sectional nature.

Disclosures: Blaha, Mirbolouk and Orimoloye report they received a grant from the FDA to study tobacco regulatory science. Blaha reports he has served on the FDA’s Tobacco Product Scientific Advisory Committee.

Electronic cigarettes include a diverse group of battery-powered devices that vaporize nicotine-containing, often flavored solvents for inhalation. Initially, these devices were proposed as an alternative cessation strategy for cigarette smokers who are unable to quit using conventional cessation therapies.

However, since their introduction into the U.S. market in 2006, e-cigarettes have gained popularity, especially among youth, and their use (also called vaping) has considerably extended to “never smokers.” In a recent study, it was estimated that as of 2016, almost 2 million U.S. adults who had never smoked cigarettes were current users of these products. With the recent introduction of newer brands (eg, Juul), which can be used more discreetly among teenagers, evidence suggests that e-cigarette use prevalence has trended upward, particularly in youth.

Olusola A. Orimoloye

In 2016, the FDA extended its regulatory authority to e-cigarettes through the Deeming Rule. However, to guide further regulation of these products in adults, the FDA requires actionable evidence on their health effects, including any potential CV toxicity.

Mohammadhassan Mirbolouk

Vaping and cardiotoxicity

There are many constituent components of inhaled e-cigarette vapor that may be potential candidates for CV toxicity (Table). These include toxic metals such as lead, nickel and chromium; volatile organic compounds (VOCs) such as acrolein, flavoring derivatives; and nicotine, a known trigger for myocardial ischemia and infarction due to stimulation of the sympathetic nervous system. Comparative studies of VOC exposure across a range of tobacco product use behaviors suggest that sole e-cigarette users have significantly greater levels of exposure to VOCs than nonusers of tobacco products, albeit lower than in conventional cigarette smokers.

Michael J. Blaha

Given the popularity of e-cigarette use and the aforementioned concerns about potential CV toxicity, there has therefore been considerable interest in understanding CV risks that may attend the use of these products, in absolute terms, and relative to conventional cigarette smoking.

E-cigarettes and CV risk

Unfortunately, according to the 2018 report of the National Academies of Sciences, Engineering, and Medicine, titled “Public Health Consequences of Electronic Cigarette Use,” there is, as yet, no available evidence as to whether e-cigarette use is associated with clinical CV outcomes such as CHD, peripheral artery disease or stroke, and subclinical disease, including carotid intima-media thickness and coronary artery calcification.

Despite the general availability of laboratory-based animal studies, and short-term exposure studies that have highlighted unfavorable effects of e-cigarette exposure on short-term outcomes such as heart rate variability, oxidative stress and endothelial dysfunction, critical prospective epidemiologic data are sparse (Table).

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There are many contributory factors to the paucity of such data. First, most e-cigarette users are young people who have very low baseline risk for subclinical or clinical CVD outcomes. Secondly, given the temporal proximity of their introduction into the market, it is possible that most users have not used these products for long enough to reasonably accumulate excess risk. Finally, the overall pattern of use of these products is immensely variable, with many users cycling rapidly between e-cigarettes and other tobacco products, experimenting with their use, being occasional users, or settling into the use of multiple products. Indeed, studies show that dual use of e-cigarettes and conventional cigarettes is the predominant pattern of e-cigarette use.

Potential relationships

In the absence of longitudinal data, two cross-sectional studies assessing associations between e-cigarette use and classical CVD outcomes have been conducted. In the most recent of these studies, Albert D. Osei, MD, MPH, postdoctoral researcher at the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, and colleagues examined the association between self-reported use of e-cigarettes and a CVD composite of angina, MI and stroke using data from about 450,000 participants of the Behavioral Risk Factor Surveillance System, a large nationally representative sample of U.S. adults.

The researchers found no significant association between e-cigarette use and CVD among never smokers, but they reported a statistically significant 36% higher odds of CVD in dual users of e-cigarettes and conventional cigarettes compared with those who only used conventional cigarettes. Additionally, the authors showed a graded increase in odds of CVD with increasing frequency of e-cigarette use, reporting significantly greater odds in daily users than in occasional users.

The effect of confounding and reverse causality may be difficult to exclude in their study, but it represents a crucial first step to understanding potential CV risks that e-cigarettes may pose.

Ongoing studies in the e-cigarette/CVD space are looking to explore the relationship between e-cigarette use and mediators of CV risk, which are known to appear early in the atherosclerotic process. Some of these include inflammatory markers, markers of oxidative stress and measures of vascular reactivity. Assessment of the relationship between e-cigarette use and these relatively proximal measures may help to address confounding in prior human studies and to inform regulatory and clinical decision-making.

Implications for clinicians

Current evidence suggests that e-cigarettes may be useful as cessation aids, but with important drawbacks. A recent multicenter, pragmatic trial by Peter Hajek, PhD, professor of clinical psychology and director of the Health and Lifestyle Research Unit at the Wolfson Institute of Preventive Medicine at Queen Mary University of London, and colleagues found e-cigarettes to be more effective for smoking cessation than nicotine replacement therapy (18% abstinence rate in e-cigarette-users vs. 9.9% abstinence rate in nicotine replacement therapy users) during a 1-year period, when both products were accompanied by behavioral support. However, it is important to interpret these results in the context of the differential pattern of long-term use observed among e-cigarette users in the study. Although 80% of those who “quit” smoking using e-cigarettes were still using e-cigarettes, only 9% of those who quit using nicotine replacement therapy were still on therapy at the end of the study. This finding raises significant concerns about the likelihood and implications of long-term use and continued addiction to nicotine in those who quit smoking using e-cigarettes.

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In the context of paucity of data about long-term consequences of e-cigarette exposure, it is important for clinicians to carefully weigh the potential risks of sustained use of these products against short-term benefits of cigarette smoking cessation, and to only recommend these products (with caution) when first-line options such as FDA-approved cessation therapies have been exhausted.

Longitudinal studies needed

The popularity of e-cigarettes has increased over time, but very little is known about CV risks that may be associated with their use. Nevertheless, since evidence suggests elevated levels of exposure to potential cardiotoxic substances in e-cigarette users compared with never users of tobacco products, it is reasonable to conclude that e-cigarette use in nonsmoking youth is almost certainly harmful, and should be discouraged.

Crucially, longitudinal studies are needed to definitively assess potential CV harm that may attend the use of these products, as the few studies that have demonstrated associations between e-cigarette use and clinical outcomes such as CHD and stroke have been limited by their cross-sectional nature.

Disclosures: Blaha, Mirbolouk and Orimoloye report they received a grant from the FDA to study tobacco regulatory science. Blaha reports he has served on the FDA’s Tobacco Product Scientific Advisory Committee.

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