Wen 丨壹贰叁
Editor丨壹贰菁
Preface:
Smoking is an important cardiovascular health risk factor. While the number of smokers has declined over the past few decades, hookahs and e-cigarettes partially compensate for this health benefit. E-cigarettes may produce highly addictive dual users (smoking and vaping). E-cigarettes do not appear to be a healthy alternative to smoking, although they may be less harmful.
E-cigarettes can cause oxidative stress, inflammation, endothelial dysfunction, and related cardiovascular sequelae. This is mainly due to the large overlap of toxic compounds in vapors compared to tobacco smoke and, accordingly, the pathological characteristics of the mechanism between vapor and smoking.
The main toxins in steam are reactive aldehydes such as formaldehyde and acrolein, while toxic mixtures in smoke are more complex, including particulate matter, reactive gases, transition metals, volatile organic compounds, and N-nitrosamines.
However, it appears that the degree of impairment of endothelial function by the two lifestyle drugs is very similar, which may be due to the role of oxidative stress as the main pathological mechanism mediating endothelial dysfunction and vascular damage.
The main sales argument for e-cigarette use is that they help quit smoking and get rid of nicotine addiction, which may be wrong because e-cigarettes instead seem to trigger the opposite – younger entry age and more frequent use. We summarize the adverse health effects of tobacco cigarettes and e-cigarettes, highlighting the adverse effects on endothelial function and cardiovascular health.
First, clinical evidence of cardiovascular risk of e-cigarettes
There is substantial evidence that the toxic compounds produced in e-cigarettes and smoke have serious harmful effects on cardiovascular health, primarily by increasing oxidative stress and causing endothelial dysfunction. However, research on the long-term effects and cardiovascular risks of e-cigarettes is limited and controversial.
Two large clinical trials showed that e-cigarettes were associated with a high risk of myocardial infarction, with an odds ratio of 2.11. However, results vary when aggregated analysis or looking at previous e-cigarette use. In contrast, a systematic review and meta-analysis concluded that e-cigarettes severely impair heart rate and blood pressure, but still show benefits from switching from tobacco to e-cigarettes.
Similarly, when switching to e-cigarettes, the cardiovascular disease burden of former smokers decreased, but there were no clear benefits in blood pressure and heart rate. It is worth noting that most e-cigarette users are former tobacco cigarette users or dual users, and e-cigarettes may help people who started smoking from non-smokers.
Recent large-scale clinical trials have not reported a significant increase in the risk of e-cigarette use. A large cohort of 449,092 U.S. participants found no association between e-cigarette use and widespread cardiovascular disease (syndrome of coronary heart disease, myocardial infarction, or stroke) in people who had never smoked.
There was no difference in the risk of cardiovascular disease (myocardial infarction or need for bypass surgery, heart failure, other heart disease or stroke or combination of myocardial infarction, heart failure or stroke) between participants who used e-cigarettes only and those who did not use e-cigarettes.
In addition, there is a trend that e-cigarette use alone is associated with a 30% to 40% lower risk of cardiovascular disease compared to smoking alone. There was also no difference in cardiovascular risk when e-cigarettes alone were compared with no cigarettes and e-cigarettes. Conversely, dual use of cigarettes and e-cigarettes was associated with an increased risk of cardiovascular disease compared to non-use.
Overall, there were significant differences in the primary outcomes of these clinical studies for the following reasons. The study mentioned above was a meta-analysis of acute intervention and observational studies that concluded that e-cigarette use increases the risk of cardiovascular disease.
Another report represents a controlled trial of switching from combustible tobacco cigarettes to e-cigarettes. The primary outcome was improvement in flow-mediated dilation after 1 month follow-up. However, none of the secondary outcomes improved (e.g., pulse wave velocity, heart rate, markers of circulatory inflammation).
Since nicotine is a known developmental poison, vaping during pregnancy is expected to pose a risk to the fetus. Only limited observational studies have been conducted in humans, and there are no data on cardiovascular development. Animal studies provide more information and point to changes in cardiovascular and lung function in offspring.
Another key point is the impact of secondhand smoke. These studies on second-hand e-cigarette vapor are few and focus only on chemical composition and prevalence, rather than the effects on the heart and lungs. However, one study showed an association between second-hand e-cigarette vapor and asthma events in adolescents.
Second, oxidative stress and endothelial dysfunction
The pathological mechanisms by which smoking leads to cardiovascular disease (CVD) and death are complex and only partially characterized. Endothelial dysfunction, most likely mediated by oxidative stress, is an early functional parameter reflecting cardiovascular impairment in smokers. Endothelial dysfunction is also considered an early predictor of future cardiovascular events or general poor cardiovascular outcomes.
Human endothelial function is often determined by flow-mediated dilation (FMD) of the forearm, a technique in which restarted blood flow after occlusion (ischemia) triggers endothelium • Mechanical stimulation and reperfusion-dependent stimulation caused by NO formation and vasodilation (= hyperemia).
Functional endothelial cells are key to regulating vascular tone, inflammation, vascular growth, platelet aggregation, and coagulation. Endothelial production of vasodilators mediating significant anti-atherosclerotic and anti-aggregation effects, such as nitric oxide (NO) and prostacyclin, is the central mechanism for ensuring a healthy vasculature.
Endothelial dysfunction is a hallmark of all cardiovascular diseases, the basis of which is dysregulated biochemical pathways in the endothelium. The pathophysiology behind endothelial dysfunction is complex, but the abundance of reactive oxygen species (ROS) in the vasculature is high, derived from ROS sources.
For example, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, mitochondria, and uncoupled endothelial nitric oxide synthase (eNOS) represent the key pathological mechanisms of all cardiovascular diseases associated with endothelial dysfunction.
Few central oxidative stress-mediated pathologic responses in the vascular system are thought to be the main cause of endothelial dysfunction, increased blood pressure, atherosclerotic changes, and ischemic events.
In addition to these major oxidative stress-mediated pathways leading to cardiovascular damage, imbalances in fatty acid metabolism and signaling are major causes of impaired vascular/endothelial homeostasis.
For example, altered epoxyeicosatrienoic acid (EETs) formation by activating soluble epoxy hydrolases, enhanced thromboxane/prostaglandin endoperoxide H2 (TP) receptor signaling, and impaired endothelial-derived hyperpolarizing factor (EDHF) synthesis, which may itself contribute to ROS formation.
Finally, many other redox processes are associated with dysregulation of vasoactive mediators, such as glycocalyx modification, endothelial permeability, inflammation, and thrombosis.
Third, the effect of e-cigarette vaporization on endothelial dysfunction
An inherent problem with the effects of e-cigarettes on endothelial function research is that published research focuses on short-term effects. There are also problems when comparing studies due to differences in the methods used to assess endothelial function, study populations (e.g., former smokers, actual smokers, or never-smokers), the technical setup of the e-cigarette device used, the liquid composition (nicotine content and flavor), and the evaporation protocol.
However, there is consensus on the potential health risks of e-cigarette use, in part due to the association of ventilator-associated pneumonia with endothelial dysfunction.
One small cohort study directly compared the adverse effects of acute vaping and smoking on endothelial function (measured by FMD) with no markers of bioavailability and oxidative stress, and no significant difference in adverse effects between acute smoking and vaping. Others are seeing similar trends, but the impact of tobacco smoke is more pronounced.
In addition, in healthy smokers, acute vaping vaporization led to endothelial dysfunction (measured by FMD and FMC), increased arterial stiffness (PTT and PWV), increased heart rate, and sympathetic vascular activation, which others generalized using nicotine-containing e-cigarette liquid, but no effect in the absence of nicotine.
A study of healthy smokers compared the short-term effects of thermocombustible devices, e-cigarettes, and tobacco cigarettes and found that FMD was impaired in all three groups, however, thermocombustible devices and e-cigarettes had particular advantages over smoking.
Animal data show that tobacco and e-cigarettes have similar effects on endothelial function. Notably, an 8-month study of chronic vaping versus smoking in mice showed that the two lifestyle drugs had comparable damage to arterial stiffness and endothelial function in ex vivo blood vessels.
Short-term vaping in rats using high nicotine concentration e-cigarette liquid (JUUL) showed a considerable degree of endothelial dysfunction, comparable to the damage to FMD from normal nicotine concentration liquid or classic tobacco cigarettes.
Our data suggest that exposure to e-cigarette vapor for up to 5 days in mice leads to massive endothelial dysfunction, heart/cerebrovascular ROS formation, eNOS uncoupling, increased phagocytes NADPH oxidase (NOX-2) activity, increased endothelin-1 expression, and acrolein-protein adduct formation.
Cardiovascular damage is more pronounced when using nicotine-free fluids, and in vitro deletion of Nox2 and pharmacological NOX-2 inhibition are prevented by genes. The lack of NOX-2 inhibits oxidative bursts of blood leukocytes, while e-cigarette vapor exposure increases oxidative bursts of blood leukocytes.
In addition, endothelial dysfunction and elevated systolic blood pressure in mice exposed to e-cigarette vapor were normalized by genetic approach to Nox2 deletion. In addition, vape vapor exposure increased vascular oxidative stress (measured by two separate methods), which was prevented in the absence of NOX-2.
We found that macitentan blocks endothelin-1 receptor signaling and bepridil activates the antioxidant and protective transcription factor FOXO3, which are potential pharmacological targets for mitigating vapa vapor-related cardiovascular damage. Both drugs protect against endothelial dysfunction, increased blood pressure, and vascular oxidative stress caused by e-cigarette vapor.
Returning to the main mechanism of endothelial/vascular dysfunction presented above, for e-cigarette vapor exposure, it has been shown that more protein tyrosine residues are nitrified, suggesting higher levels of pernitrite and nitric oxide oxidative breakdown, supporting pathological mechanisms 1 and 4.
Endothelial dysfunction and nNOS uncoupling support pathological mechanisms in e-cigarette-exposed mice2 and sympathetic neurovascular activation, increased endothelin-1 expression and macitentan blockade pointing to the pathological mechanisms of vaping healthy subjects3.
Other studies have shown NADPH oxidase (NOX-2) activation, increased vascular ROS formation, elevated 3-nitrotyrosine levels, decreased vascular nitric oxide bioavailability, decreased BH4 levels, and eNOS uncoupling due to e-cigarette vapor exposure, all of which are associated with endothelial dysfunction and increased blood pressure.
In addition, increased inflammation and advanced glycation end-product receptor (RAGE) signaling were observed in cultured endothelial cells exposed to e-cigarette vapor. Blood clots worsen in mice exposed to steam and platelet function is enhanced, which may indicate impaired prostaglandin synthesis.
These pathological features are also associated with smoking-induced oxidative stress, NADPH oxidase activation, and eNOS uncoupling, and activation of the renin-angiotensin-aldosterone system (RAAS) may be predominantly mediated by nicotine.
A study of retinal microcirculation in e-cigarette users showed that the density of foveal vessels was significantly reduced, and the area of foveal unvascular areas increased. A study in mice showed that after e-cigarette exposure, the regulation of several genes related to blood-brain barrier function in the brain's microvessels changed.
Studies have also shown that large catheter vessels (determined by, for example, flow-mediated dilation of the brachial artery) are negatively affected by e-cigarette use. In summary, e-cigarettes may impair catheter and resistance arterial function. However, we still don't know the exact mechanism that explains the interaction between macrovascular and microvascular exposure environments.
Fourth, toxic compounds and pathogenic mechanisms
The pathological mechanism of cardiovascular damage caused by e-cigarettes is far less clear than that caused by smoking. In addition, the clinical evidence for e-cigarettes is not as strong as the clinical evidence for tobacco use. However, the formation of ROS (oxidative stress), inflammation and endothelial functional impairment are the main factors that mediate the harmful effects of e-cigarette vaping.
Impairment of endothelial function caused by smoking has been reported in 1993 to be improved by emergency vitamin administration, providing indirect evidence for the role of oxidative stress in smoking-mediated endothelial dysfunction. Different methods measured very similar damage to endothelial function from e-cigarette vapor.
Vascular damage and endothelial dysfunction caused by adverse lifestyle risk factors, such as smoking and evaporation, can be best explained by the apparent overlap of toxic compounds in smoke and vapor. A list of known toxic compounds in combustible cigarette smoke is found, while toxins in e-cigarette vapors and liquids are present.
However, the characteristics of toxic compounds in vapors and smoke change with basic principles: smoke is formed by the combustion of tobacco, which during evaporation is produced at a much higher temperature than in the heating coil of an e-cigarette. Pyrolysis produces more harmful compounds and active compounds than the relatively moderate temperatures achieved during steam generation.
However, it is known that temperatures of > 200 °C can be easily reached during the production of steam, which is sufficient to cause fragmentation and oxidation of the main components propylene glycol and glycerol in the liquid to form reactive aldehydes and ketones [53]. The fragmentation and oxidation of the components of the e-cigarette liquid depends not only on the heating temperature, but also on the catalytic performance of the metal surface in the e-cigarette heating element.
In commercial liquids, nicotine and fragrances cause a large number of toxins that are more complex because these additives produce secondary toxins during heating. In our study, we prevented these further complications only by comparing the health effects of primary fluids with or without nicotine and without any flavoring compounds.
The toxicity of tobacco smoke is mainly composed of transition metals, carbon monoxide and other toxic gases, N-nitrosamines, solid particulate matter (carbon/soot particles), volatile organic compounds (VOCs, such as benzene), and polycyclic aromatic hydrocarbons (PAHs, such as benzo[a]pyrene).
In contrast, the most critical toxins in e-cigarette vapor are reactive aldehydes, such as formaldehyde and acrolein, and small amounts of transition metals. However, N-nitrosamines and volatile organic compounds are only detected in trace concentrations in steam.
The above-mentioned toxic compounds in e-cigarette vapor are effective inducers of oxidative stress and inflammatory response, accompanied by subsequent progression of endothelial dysfunction and atherosclerosis, all of which increase cardiovascular and cerebrovascular risks.
Our mouse studies have shown that reactive aldehydes, namely formaldehyde and acrolein, are the most harmful in mediating the damaging effects of e-cigarette vapor on the vasculature. Substantial overlap of toxins in tobacco smoke and e-cigarette vapor, which explains partially shared pathological mechanisms centered on oxidative stress and inflammation.
The major toxic components of tobacco smoke, such as particulate matter, toxic gases, volatile organic compounds, polycyclic aromatic hydrocarbons, and transition metals, have been shown in the past to cause oxidative stress and inflammation in cells and tissues, which are potential triggers for endothelial dysfunction and vascular damage.
As a result, there is significant overlap in the markers of impairment from smoking and evaporation, as well as some overlap in reported significant adverse health effects. In addition, genetic or pharmacological antioxidant interventions showed similarities in health benefits between smoking and e-cigarettes.
epilogue
The use of tobacco products causes more than 8 million preventable deaths each year, a large proportion of which are cardiovascular diseases. Although the number of smokers has decreased in recent years, the health benefits of this reduction are partially compensated for by the increase in the number of users of hookah and e-cigarettes and the lower entry age.
The pathological mechanism of e-cigarette smoke and smoking is characterized by the same pathological mechanism, especially oxidative stress and inflammation, mainly due to the inevitable overlap of toxic compounds in smoke and vapor. Both lifestyle risk factors have been reported for endothelial dysfunction and cardiovascular impairment.
While e-cigarettes appear to be less harmful than tobacco cigarettes (because vapors contain fewer toxic compounds), only a handful of long-term human studies are available, making it impossible to reliably estimate the health risks associated with vapor devices. These facts and the lower age of e-cigarette use require it to be strictly regulated.