This review comprehensively summarizes both preclinical and clinical data on the CV effects of e-cigarette use. CV effects of e-cigarette constituents as well as of e-cigarette exposure are reviewed. With poll

Cardiovascular risk of electronic cigarettes: a review of preclinical and clinical studies
Literature - Buchanan ND, Grimmer JA, Tanwar V et al., - Cardiovasc Res 2019. cvz256, https://doi.org/10.1093/cvr/cvz256

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Introduction

Electronic cigarettes (e-cigarettes) are popular because of their perceived safety when compared with traditional cigarette smoking. As a consequence, they not only appealing to smokers attempting to quit, but their use increases among non-smokers, including teens and young adults. E-cigarettes have been advertised to contain fewer toxic substances than combustible cigarettes, but they do contain potentially toxic compounds that have yet to be thoroughly studied.

Design of e-cigarettes

Since its introduction, various types of e-cigarettes have been developed, with very little regulation. In addition to first-generation disposable ‘cigalikes’, second-generation rechargeable e-cigarettes and third-generation tank devices are available, and pod-based devices such as ‘JUUL’ now form the largest part of the e-cigarette market. The latter devices consist of a lithium battery power source, a cartridge containing e-liquid and an atomizer or heating device that vaporizes the liquid. Popularity of the pod-based devices is thought to lie in their discrete design, high nicotine concentrations and flavorings.

Potential cardiovascular toxicity of e-cigarette constituents

Vapor composition is dependent on many variables, including the propylene glycol to glycerine ratio (solvents), manufacturer of the e-liquid, type of e-cigarette, coil temperature, air flow rate, nicotine content and the added flavors. A common finding in analyses show, however, the presence of nicotine, carbonyl compounds, particulate matter, metals and flavoring compounds in significant concentrations. The article includes a detailed table of the available evidence from preclinical and clinical studies showing acute and chronic CV effects of e-cigarette exposure.

Nicotine

Nicotine is known to have various effects on the CV system. For instance, through binding to nicotinic cholinergic receptors, it stimulates the sympathetic nervous system. This affects hemodynamic mechanisms. Animal models show that through causing fibrosis or inducing fluctuations in uterine artery blood flow, arrhythmias can occur, as well as fluctuations in systolic BP. Animal studies have also revealed myocardial remodeling upon exposure to nicotine. Conflicting data have been published on the effect of nicotine on platelet activation.

Some studies suggest that plasma nicotine levels are lower in e-cigarette users than after traditional cigarettes. It should be noted that nicotine content varies among devices and has increased. The highest concentrations have hardly been studied to date.

Carbonyl compounds and oxidizing agents

The main carbonyl compounds found in e-cigarette vapor are formaldehyde, acetaldehyde and acrolein, which are thought to result from the thermal decomposition of propylene glycol and glycerine and some flavorings. These compounds are known to cause oxidative stress and inflammation. Concentration of these compounds increases with higher battery voltage and higher coil temperature.

Acrolein impairs the antiatherogenic function of HDL-c. Simultaneously, it disturbs endothelial cell function, which further contributes to atherogenesis. Animal studies suggest an effect of acrolein on myocardial contractility and metabolism, and activation of platelets towards a prothrombotic state. In addition to formaldehyde being classified as a carcinogen, animal studies have demonstrated acute pumping failure, and increased platelet counts and oxidative stress in cardiac tissue in response to exposure. Exposure to acetaldehyde led to fewer and damaged myocardial mitochondria. Systemic effects upon inhalation of acetaldehyde may differ from these observations in animal studies, but there is a clear rationale to study the effect on cardiac mitochondria.

Particulate matter

Ultrafine (PM0.1) and fine (PM2.5) particulate matter in e-cigarettes have been linked to atherosclerosis, through coronary heart disease and hypertension, through direct and indirect mechanisms. Both particle sizes can pass through the alveolar/endothelial interface, into the systemic circulation, where they can directly exert effects on the heart, vasculature and other organs.

Metals

Various results on the types and concentrations of metals in vapor have been published. A recent review on exposure to metals based on extreme e-cigarette use (1200 puffs/day), suggest that metal exposure levels are still below exposure guidelines. Overall exposure is not expected to be of harm in those switching from traditional to e-cigarettes. For never-smokers, however, it represents an unnecessary new source of exposure. Moreover, metals can act as a catalyst in the oxidative reactions of cellular proteins by compounds in cigarette smoke, which may be similar for e-cigarette constituents.

Flavorings

Many of the chemicals used as flavoring are deemed safe via ingestion. Little Is known, however, about their effects following chronic inhalation. An example for which ingestion is safe is cinnamaldehyde, but its inhalation induces dysfunction of pulmonary immune cells. Studies in treated cells have shown that flavorings induce reactive oxygen species production and inflammatory responses. Proinflammatory and cytotoxic responses in the lungs have also been described in relation to inhalation flavorings.

Synergistic/additive effects

Isolated exposure to the above constituents does not occur for e-cigarette users. Simultaneous exposure to the different compounds likely also has additive and synergistic effects.

Experimental and epidemiological studies on the CV effects of e-cigarette use

Acute exposure effects

Few studies into chronic exposure to e-cigarettes have been conducted. Studies into acute effects typically use one-time exposure. Methodology and used products vary among studies, thus it is difficult to draw an absolute conclusion about the short-term impact of e-cigarettes on the CV system. However, currently available evidence suggests that they are not harmless.

Preclinical studies

Cytotoxicity and inflammatory effects In vitro cell studies have demonstrated that various e-cigarette extracts are cytotoxic at 50% or 100% concentration. Generally, cytotoxicity of vapors is far less than that of cigarette smoke. E-cigarette solutions or extracts also seem to induce oxidative stress and inflammation in primary lung endothelial cells. It should be noted that the concentration and contents of e-liquids and vapors in this in vitro setting differ from the heated, aerosolized and metabolized state when used in vivo. Hence, effects will likely also differ.

Cardiac development E-cigarette exposed cardiac progenitor cells showed evidence of a persistent delay in differentiation. Zebrafish showed developmental defects such as severe heart malformations, pericardial edema and reduced heart contractile function, upon exposure to cigarette or e-cigarette extracts. A control group, exposed to nicotine, did not show the developmental defects.

Platelet function Platelets from mice exposed to e-cigarette aerosol showed significant hyperactivity, thought to be mediated by PM or acrolein. Platelets from vapor extract-exposed healthy volunteers showed upregulation of proinflammatory markers and platelet activation, aggregation and adhesion were significantly enhanced. Thus, short-term exposure seems to induce a pro-thrombotic state.

Clinical studies

Heart rate and BP/hemodynamic functions E-cigarettes induce short-term elevations in heart rate and systolic and diastolic BP. They also increase sympathetic nerve activity. All of these effects are attributed to the vasoactive effects of nicotine. Current devices with higher nicotine content have been shown to exert effects similar to traditional cigarettes.

Oxidative stress, endothelial dysfunction and vascular injury Blood samples of healthy volunteers exposed to e-cigarettes showed higher levels of endothelial progenitor cells after 1 hour. These cells are important for endothelial repair and elevated levels serve as a biomarker for vascular injury. Users also show signs of increased oxidative stress, and endothelial vascular dysfunction. A study that compared nicotine-containing with nicotine-free e-cigarettes found that the oxidative stress seemed attributable to nicotine.

Chronic exposure effects

Preclinical studies

Cardiac function A mouse study showed that chronic exposure (8 months, equivalent to ~25 years in humans) resulted in significantly increased arterial stiffness, reduced vascular relaxation to vasodilators and enhanced responses to vascular constrictor agents even at low levels of exposure. The level of vascular dysfunction observed was assessed to be similar to that seen after exposure to traditional cigarette smoking. Shorter studies confirm the effect on endothelial dysfunction, which is associated with accelerated atherosclerosis and CVD. A study in mice exposed for 3-6 months showed increased systemic inflammation, greater levels of heart fibrosis and higher SBP and a trend towards higher DPB. Another mouse study revealed formation of DNA mutagenic adducts in various tissues, including the heart.

Clinical studies

Cardiac sympathetic activity, inflammation and oxidative stress A year-long study in habitual e-cigarette users observed a shift in cardiac autonomic balance towards sympathetic predominance, compared to non-user controls. LDL oxidizability and markers of oxidative stress were also higher in e-cigarette users. Another study reported activation of the splenocardiac axis, which is an inflammatory signaling network initiated by increased sympathetic nerve activity, and involved in atherogenesis and acute MI. An observational study showed a 1.79 times higher risk for daily e-cigarette users to experience an MI than those who never used e-cigarettes, after accounting for other risk factors including cigarette smoking. These findings need to be confirmed in other studies.

The ongoing controversy/e-cigarette debate

Studies showing no adverse effects give rise to the controversy regarding risk associated with e-cigarette use and advocates for its use as a tool for smoking cessation.

Preclinical studies

A study evaluating the effect of cigarette smoke extract and e-cigarette aerosol extract on stress response, found that e-cigarette aerosol does not elicit the same cellular stress reactions as cigarette smoke. The authors concluded that e-cigarettes could be used as a substitute for conventional cigarettes. Another study showed that cigarette smoke, but not e-cigarettes, had an inhibitory effect on endothelial migration in the scratch wound assay. These in vitro models suggest that e-cigarettes could be effective as a harm-reduction alternative to traditional cigarettes. The findings are, however, contrasting with the majority of studies to date.

Clinical studies

A study in healthy chronic smokers (≥5 cigarettes per day for ≥2 years) showed no difference in effect on arterial stiffness in those smoking a traditional cigarette or e-cigarette. In another study, participants who either switched completely or partly, or completely discontinued tobacco and nicotine use, all used e-cigarettes for 5 days and showed no differences with regards to BP or heart rate, negative respiratory health outcomes or serious adverse health events. Those who switched to e-cigarettes or ceased smoking altogether even showed lower BP and heart rate and better lung function. Another study also showed that smokers who reduce or quit smoking by switching to e-cigarettes may lower their SBP in the long term.

These results have been used to advocate for the potential of e-cigarettes as a safer alternative to tobacco cigarettes.

Limitations

It is important to realize that many clinical studies had low statistical power and enroll volunteers who were previous or current smokers, which impacts the validity for other groups in society, such as youth who never smoked before. As mentioned, the variety of study protocols and products used limit the replicability and make it difficult to draw concrete conclusions. The use of older e-cigarette models also limits the generalizability of many findings.

Conclusion

The reviewed data suggest that there is not sufficient data to conclude that e-cigarette use may lead to fewer negative CV effects than conventional cigarettes. Instead, the presented studies show that e-cigarettes can induce negative CV effects through various mechanisms such as oxidative stress, inflammation, DNA damage, arterial stiffness, and altered hemodynamics and platelet activity. Thus, great caution and hesitation remains valid concerning e-cigarette use until its health risk profile is better established. Studies should not only focus on the effect of nicotine in the e-liquid, but should also investigate the systemic effects of inhalation of flavoring molecules. Studies should also explore other populations, including in utero exposure to examine their perceived safety as a cigarette cessation method during pregnancy.

Find the review online at Cardiovasc Res