An Update on Biological and Clinical Associations between E-Cigarettes and Myocardial Infarction

This report aims to update readers of this journal on the biological and clinical associations between e-cigarettes and myocardial infarction (MI), and extends on the report published here several years ago.[1] A recent electronic search within the Global Health Data Exchange repository,[2] reveals that tobacco smoke may currently cause as many as 7.1 million deaths each year worldwide, accounting also for as many as 182.5 million disability-adjusted life years. Previous evidence that shifting from conventional (i.e., combustible) to e-cigarettes may improve smoking cessation has raised sizable enthusiasm that the use of these devices would allow gradually quitting tobacco smoking and thereby reducing the many and multifaceted associated health risks.[3] Nevertheless, growing evidence now underpins that the use of e-cigarettes is not as safe as was commonly propagandized and perceived.[4]

Huge emphasis has recently been given to the so-called vaping-related pulmonary disease,[5] encompassing a kaleidoscope of acute toxic lung parenchyma injuries, which have contributed to cause a substantial number of deaths. The health hazards have been mostly attributed to some inhaled compounds contained in the fluid of e-cigarettes, especially organic volatile compounds such as toluene and benzene, particles, carbonyls, trace metals, and nicotine, along with potential contaminants such as fungal glucans and bacterial endotoxins.[5] Besides the severe, often life-threatening vaping-induced lung injury, convincing evidence is also accumulating that the use of e-cigarettes may be associated with an enhanced risk of ischemic heart disease. Therefore, this succinct update on recently published evidence reporting biological and clinical associations between e-cigarettes and MI aims to fill any gaps related to lack of reliable epidemiologic studies on cardiovascular complications of e-cigarettes at the time of the previous 2014 publication.[1]

Pieri et al, also in 2014, developed a mathematical model for establishing the number of conventional (i.e., combustible) cigarettes that a smoker would need to quit to obtain significant health benefits after shifting to e-cigarettes.[6] Their desolate conclusion was that halving any number of conventional cigarettes per day would not be effective to significantly decrease the risk of MI. Nevertheless, more solid evidence has since become available with publication of large cross-sectional population studies.

Alzahrani et al performed a National Health Interview Survey (NHIS) in the U.S. first using years 2014 (n = 36,697) and 2016 (n = 33,028) data, to explore potential associations between the risk of developing MI deriving from combustible cigarette or e-cigarette use.[7] Occasional e-cigarette smokers were found to have a cumulative risk of MI globally comparable to that of nonsmokers (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 0.83–1.62). Nevertheless, such risk achieved statistical significance in daily e-cigarette users (OR, 1.79; 95% CI, 1.20–2.66), which was lower than that of daily combustible cigarette smokers (OR, 2.72; 95% CI, 2.29–3.24). Interestingly, the same team of authors updated their results in a subsequent letter to the editor, including data from the year 2015 (the number of patients was not specified),[8] and reporting higher cumulative risk estimates for MI, with an OR of 1.49 (95% CI, 1.06–2.09) for occasional e-cigarette smokers and 2.14 (95% CI, 1.41–3.25) in those using e-cigarettes daily. Vindhyal et al then recently published NHIS results including 2014 (n = 36,697), 2016 (n = 33,028), and 2017 (n = 26,742) data,[9] concluding that e-cigarette users not only have an over 50% higher risk of developing MI (OR, 1.56, 95% CI, 1.45–1.68), but also a 30% higher risk of developing stroke (OR, 1.30, 95% CI, 1.20–1.40) compared with nonusers, thus reinforcing similar findings on the same study population limited to data collected in the years 2016 and 2017.[10]

These important findings have also been confirmed in another large U.S. population-based longitudinal cohort study published by Bhatta and Glantz and involving as many as 32,320 subjects.[11] Overall, the risk of MI was found to be nearly twice as high in occasional e-cigarette users than in never users (OR, 1.99; 95% CI, 1.11–3.58), increasing further to approximately 2.2-fold (OR, 2.25; 95% CI, 1.23–4.11) in those who declared daily use of e-cigarettes. For comparison, the risk of MI in subjects who occasionally or daily used combustible cigarettes was marginally higher, that is, 2.38-fold (OR, 2.38; 95% CI, 1.40–4.06) and 2.95-fold (OR, 2.95; 95% CI, 1.91–4.56), respectively.

More recently, Osei et al performed a large cross-sectional telephone survey study including as many as 449,092 participants who provided detailed, self-reported information on several behavioral variables, including use of e-cigarettes, between the years 2016 and 2017.[12] A composite of self-reported coronary heart disease, MI, or stroke was considered as the main outcome. Although the primary composite outcome did not differ between never e-cigarette smokers and current daily e-cigarette users (OR, 1.35; 95% CI, 0.74–2.46), the risk of cardiovascular disease was found to be 36% higher in dual users of combustible and e-cigarettes compared with current combustible cigarette smokers alone (OR, 1.36; 95% CI, 1.18–1.56). Such risk was understandably higher in daily dual users of combustible and e-cigarettes smokers (OR, 1.59; 95% CI, 1.20–2.08) than in occasional dual users (OR, 1.30; 95% CI, 1.12–1.52). An even higher risk of prematurely developing the primary endpoint (i.e., cardiovascular disease at < 55 and < 65 years old in men and women, respectively) was also noted in dual users (OR, 1.45; 95% CI, 1.20–1.74).

Finally, the U.S. Centers for Disease Control and Prevention has also recently published an abstract with the results of the 2016 Behavioral Risk Factor Surveillance System study, a very large annual survey which included 410,651 responders (66,795 regular e-cigarettes users and 343,856 controls).[13] E-cigarettes users were found to have a significantly enhanced risk of angina and/or coronary heart disease (OR, 1.4; 95% CI, 1.35–1.46), MI (OR, 1.59; 95% CI, 1.53–1.66), and even stroke (OR, 1.71; 95% CI, 1.64–1.8) compared with nonusers.

As regards the putative biological mechanisms linking e-cigarette use with MI, the results of a very interesting study have been recently been published by Qasim et al.[14] Briefly, a passive vapor inhalation system (containing nicotine 18 mg, with 30% propylene glycol and 70% vegetable glycerin) mimicking ex vivo real-life human e-cigarette exposure has been developed for use in mice. The first important finding was that e-cigarette exposure was actually capable of systematically delivering nicotine to mice. The average plasma concentration of the nicotine metabolite cotinine was 54 ± 4 ng/mL, thus comprised within the range of values of this compound normally found in humans using e-cigarettes (i.e., 30–250 ng/mL). As regards primary hemostasis, the platelet count did not vary significantly after e-cigarettes exposure, while the bleeding time was found to be 10-fold shortened (52 ± 18 vs. 585 ± 15 seconds). In a ferric chloride carotid artery injury-induced thrombosis model, e-cigarette exposure was also associated with an approximately threefold shortened occlusion time (248 ± 69 vs. 612 ± 67 seconds). Platelet biology was dramatically perturbed toward a hyperaggregation state by e-cigarette exposure, as revealed by elevated adenosine diphosphate- and U46619-triggered platelet aggregability, enhanced integrin glycoprotein IIb–IIIa activation, augmented P-selectin, and phosphatidylserine expression on platelet surface, as well as increased Akt and extracellular signal-regulated kinase phosphorylation. Similar findings were published by Nocella et al, who explored the impact of e-cigarette vapor (containing 16 mg of nicotine) with a single-blind crossover study including 40 healthy participants.[15] Notably, the concentration of soluble CD40 ligand (sCD40L) and soluble P-selectin increased by 1.7- and 2.0-fold within 5 minutes after e-cigarette use. The analogous variations of sCD40L and soluble P-selectin 5 minutes after smoking a combustible cigarette were 2.0- and 2.7-fold, respectively. Collagen-triggered platelet aggregation was also enhanced immediately after e-cigarette use (1.16- vs. 1.39-fold increase after combustible cigarette). All these changes were magnified in the nonsmokers subgroup (n = 20). Overall, these data confirm previous in vitro evidence, that exposure to e-cigarette vapor extracts enhances platelet activation, adhesion, and aggregation.[16] [17]

Taken together, these recent biological and epidemiologic findings, as briefly reviewed here, would lead us to conclude that significant associations may exist between e-cigarette use and MI ([Table 1]), which appear to be dose-dependent and potentially magnified by concomitant use of “conventional” combustible cigarettes. Although no prospective studies have been published to date that can provide stronger epidemiologic evidence on this matter, the results of some biological investigations seem to support this association, whereby a prothrombotic phenotype (especially characterized by enhanced platelet activation, and possibly increased adhesion and aggregation) may develop after exposure to nicotine-containing e-cigarette vapors. Although it is premature to currently draw definitive conclusions, also noting that the harmful effects of e-cigarettes appear globally lower than those causes by conventional combustible cigarettes, we still raise well-founded doubts that recreational use of e-cigarette is safe, so that their usage in nonsmokers should probably continue to be discouraged.

Table 1 Summary of recent cross-sectional population studies which have investigated the relationship between e-cigarette use and the risk of developing myocardial infarction (MI)

Authors	Population	Risk of MI in e-cigarette users
Alzahrani et al, 2018	n = 69,725	Occasional users: OR, 1.16 (95% CI, 0.83–1.62) Daily users: OR, 1.79 (95% CI, 1.20–2.66)
Alzahrani and Glantz, 2019[a]	n = 97,625	Occasional users: OR, 1.49 (95% CI, 1.06–2.09) Daily users: OR, 2.14 (95% CI, 1.41–3.25)
Vindhyal et al, 2019[a]	n = 96,467	Current users: OR, 1.56 (95% CI, 1.45–1.68)
Bhatta and Glantz, 2019	n = 32,320	Occasional users: OR, 1.99 (95% CI, 1.11–3.58) Daily users: OR, 2.25 (95% CI, 1.23–4.11)
Osei et al, 2019	n = 449,092	Current daily users: OR, 1.35 (95% CI, 0.74–2.46) Dual daily users: OR, 1.59 (95% CI, 1.20–2.08)
Ndunda and Muutu, 2019	n = 410,651	Current users: OR, 1.59 (95% CI, 1.53–1.66)

Abbreviations: 95% CI, 95% confidence interval; MI, myocardial infarction; OR, odds ratio.

^a This data originates from the same U.S. National Health Interview Survey (NHIS).

• References

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